Light-responsive functional nanomaterials as pioneering therapeutics: a paradigm shift to combat age-related disorders

Abstract

Aging, marked by dysregulated cellular systems, gives rise to a spectrum of age-related disorders, including neurodegeneration, atherosclerosis, immunosenescence, and musculoskeletal issues. These conditions contribute significantly to the global disease burden, posing challenges to health span and economic resources. Current therapeutic approaches, although diverse in mechanism, often fall short in targeting the underlying cellular pathologies. They fail to address the issues compounded by altered pharmacokinetics in the elderly. Nanotechnology emerges as a transformative solution, offering tissue-specific targeted therapies through nanoparticles. Functional nanomaterials (FNMs) respond to internal or external stimuli, with light-responsive nanomaterials gaining prominence. Harnessing the benefits of deep tissue penetration and ease of manipulation particularly in the near-infrared spectrum, light-responsive FNMs present innovative strategies for age-related comorbidities. This review comprehensively summarizes the potential of light-responsive FNM-based approaches for targeting cellular environments in age-related disorders, and also emphasizes the advantages over traditional treatment modalities. Specifically, it focuses on the development of various classes of light-responsive functional nanomaterials including plasmonic nanomaterials, nanomaterials as carriers, upconversion nanomaterials, 2D nanomaterials, transition metal oxide and dichalcogenide nanomaterials and carbon-based nanomaterials against age related diseases. We foresee that such advanced developments in the field of nanotechnology could provide a new hope for clinical diagnosis and treatment of age-related disorders.

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Shubham Kumar Singh

Mr Shubham Kumar Singh has graduated with Bachelor of Science in Zoology (Hons) from Kolhan University, Jharkhand (2017), and Master of Science in Zoology from Jiwaji University, Gwalior, Madhya Pradesh (2019). He has interests in neuroscience (especially neurodegenerative diseases) and cancer. Currently he is pursuing PhD in the Department of Bioscience and Bioengineering, IIT Jodhpur, Rajasthan, and his research focuses on applications of drug delivery systems in cancer and neurodegenerative diseases.

Shivay Parihar

Dr Shivay Parihar is a trained clinician and completed his MBBS from Dr S. N. Medical College, Jodhpur. He is interested in research on ageing biology and strategies to halt the ageing process. Currently, he is working on senolytic drug delivery using nanoparticles for targeting senescent cells at the Department of Bioscience and Bioengineering, IIT Jodhpur, Rajasthan.

Sanskar Jain

Mr Sanskar Jain has completed his bachelors in the triple major course of Biotechnology, Chemistry and Zoology from Christ University, Bengaluru, in 2023. He has previously worked at ASTER Labs, Bangalore, in their diagnostic wing. He also has interests in molecular biology and cytology and aims to delve deeper into the world of fundamental research. Currently he is working on developing a model BBB to test the feasibility of transport of nanoparticles through it.

Raviraj Vankayala

Dr Raviraj Vankayala is currently working as an Associate Professor in the Department of Bioscience and Bioengineering, Indian Institute of Technology Jodhpur, India. He received his BS (2004) and MS (2006) in Chemistry from Andhra University, India. He earned his PhD degree in Chemistry from National Tsing Hua University (2012), Taiwan, under the supervision of Prof. Kuo Chu Hwang. His postdoctoral studies were performed at National Tsing Hua University (2015) and University of California Riverside (2017), USA. He also worked as a Chief Technology Officer at Radoptics LLC, USA. His main research interests include nanotheranostics, biophotonics, and drug delivery in tackling various diseases.

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1. Introduction

Aging is an inherent and inevitable aspect of life, marking the progressive changes that occur in living organisms over time. Estimates have shown that an increment in life expectancy by just one year can lead to economic benefits of US$38 trillion, and by 10 years, about US$367 trillion.¹ Aging comprises of various physiological, cellular, and molecular changes that cumulatively contribute to the aging phenotype. Arising from a plethora of dysregulated cellular systems,² aging manifests as a myriad of age-related disorders, like neurodegeneration, atherosclerosis, immunosenescence, bone and muscle loss, etc.^3,4 These medical conditions account for more than 50% of all the ailments, which impose a significant burden on the health span of individuals.⁵ The various age-related problems manifest themselves in different systems causing a plethora of different diseases. Despite the broad diversity in the diseases and the systems they affect, their underlying mechanisms share common characteristics across all age-related disorders. Mainly, these disorders arise due to an interplay of dysfunctional regulatory systems as the body ages. These failures can result in aggregation of cellular materials such as proteins (such as in the case of neurodegenerative disorders) and lipids (such as in the case of atherosclerosis). Both cases show a sharp correlation between their increased incidence and the seniority of the individual.⁶ These aggregates induce and worsen another hallmark of aging which is the accumulation of senescent cells. Senescent cells are characterized by loss of cell division, inhibition of apoptosis, and the senescence-associated secretory phenotype (SASP) that promotes a pro-inflammatory environment responsible for pathologies related to aging.^2,7 This can affect the regular function of the system they inhabit as well as induce senescence in their neighbouring cells. The resultant inflammatory environment gives rise to a condition called inflammaging. As the age progresses, this mild inflammatory condition persists in the body which is present to combat infections by having a pro-inflammatory environment.⁸ Despite its protective function, inflammation can also be extremely detrimental for the aged individuals as inflammation is one of the major causes of systemic organ disorders in the elderly. Many age-related disorders have an inflammatory pathophysiology.⁹ With the gradual increase in age, the immune system of our body becomes fragile. This condition is called immunosenescence.¹⁰ As thymus deteriorates it affects T cell production and B cell function, and subsequently, antibody production. Consequently, the aging body becomes more sensitive to infections.¹¹ Tissue repair is another facet dependent on the immune responses as the repair of tissues usually begins once the inflammation has reduced, followed by migration of immune cells, and cellular proliferation.^12,13 All of these mechanisms are affected in the aging population.¹⁴

Despite sharing common pathways,^4,15 the currently prescribed therapies for the age-related disorders differ in terms of their mechanism of action, with most therapies failing to target the underlying cellular pathologies. The altered pharmacokinetic profiles of elderly patients further challenge the efficacy of conventional therapies.¹⁶ Additionally, most of the disorders are complicated due to weakened tissue homeostasis of patients caused by reduced regenerative capacities with age. The co-existence of many of these pathologies, unrelated co-morbidities and subsequent polypharmacy creates hotspots for adverse drug reactions and drug–drug interactions making the choice, dose, and duration of the prescribed drugs limited.¹⁷ Such a scenario highly demands unified therapeutic strategies that can target the common underlying cellular hallmarks of aging and be applied to multiple age-related diseases. Over the years, the field of nanotechnology has set a benchmark for achieving tissue-specific targeted therapies. Specifically, functional nanomaterials (FNMs) have been utilized for targeted drug delivery using the intracellular and extracellular biomarkers of different tissue types. They also ensure improved solubility,¹⁸ bioavailability¹⁹ and sustained release profiles of conventional medicines²⁰ compared to traditional administration techniques. With extensive potential for surface modifications, FNMs can be tailored to respond to either internal or external stimuli, such as pH, temperature, light, focused ultrasound, electromagnetic fields, etc., to exert therapeutic effects on demand.²¹ Among these, light provides several important benefits, such as minimal invasiveness, deeper tissue penetration, excellent spatio-temporal resolution, and ease of manipulation. Such remotely controllable FNMs can provide new routes towards the therapeutics of age-related diseases many of which require targeted drug delivery, long treatments, and time-controlled therapy (Fig. 1).

Fig. 1 Schematic representation of light responsive FNMs used against age-related disorders. Created from Biorender.com.

The functional requirements for nanomaterials ideal for combating age-related diseases include the ability to precisely target the pathological sites, such as arteries in atherosclerosis, joint cavities in osteoarthritis, and neurons in neurodegenerative disorders. To address these conditions effectively, we demonstrate that these nanomaterials can be conjugated with targeting peptides and chemical moieties, which selectively enhance their uptake at the sites of pathology. Herein, we review the recent developments of different types of light-responsive FNMs to combat age-related disorders. In particular, we focus on the potential advantages that light-responsive nanomaterials can offer over conventional treatment strategies. The different types of nanomaterials reviewed here include plasmonic nanomaterials, nanomaterials as carriers, upconversion nanomaterials, 2D nanomaterials, transition metal oxide and dichalcogenide nanomaterials and carbon-based nanomaterials. These light responsive FNMs can certainly guide the treatment of age-related disorders as well as improve the life expectancy globally.

2. Conventional therapies and advantages of light-responsive FNMs

The rate of aging can be controlled with the assistance of lifestyle modifications, such as caloric restriction, fasting and even exercise.²² However, the treatment of age-related disorders depends on the administration of small molecules, hormonal therapies, stem cell therapy, cytokine therapy, and antioxidants. These conventional approaches have been limited by several shortcomings. For example, small molecule-based drugs have low bioavailability and poor specificity towards the diseased site.²³ This certainly requires higher dosages of drugs for it to be available in sufficient quantities at the target site for the therapeutic effect to be observed. This is especially true for age-related neurodegenerative disorders, as small molecules are unable to cross the blood–brain barrier (BBB).²⁴ Yet, small molecules are still employed for managing neurodegenerative disorders, particularly Alzheimer's disease (AD) and Parkinson's disease (PD). Despite approval by the Food and Drug Administration (FDA) and widespread use, their efficacies are limited to symptomatic relief, with no substantial impact on disease progression. In fact, many of these therapeutics can have long-term adverse effects, including motor fluctuations and dyskinesias.^25,26 This is not limited to therapies for neurodegenerative treatments, as many of the current therapeutics for age-associated problems suffer from severe side effects. For example, treatments for osteoarthritis (OA) and osteoporosis are known to cause side effects in the gastrointestinal tract and complications in the liver.^27,28 Some conventional drugs for osteoporosis such as bisphosphonates trigger side effects such as atypical fractures and osteonecrosis of the jaw.²⁹ Apart from the side effects, high percentage of the elderly are on multiple prescription drugs, leading to drug–drug interactions which are further exaggerated by disturbed pharmacokinetics and pharmacodynamic parameters.^17,30 Absorption of drugs is also another factor which gets affected due to various age-associated factors such as decreased blood flow, reduced active transporters across the intestinal membrane³¹ and age-related changes in gastric pH.³² Furthermore, serum concentrations of drugs and their eventual distribution are affected by the altered glomerular filtration rates and fat percentages in the elderly.³¹ Similar problems arise with the cellular uptake and metabolism of the drugs as well.³³ Some of these drugs remain in the body for longer periods in the elderly which may increase the chances of drug–drug interactions.³⁰ Other limitations of conventional therapies include non-controlled and non-targeted drug release (common in atherosclerotic patients),³⁴ transport across biological barriers (prevalent in small drug molecule therapy for neurodegenerative disorders),²⁶ lack of dosage adjustment and optimization (crucial in hormone therapy) and lack of spatiotemporal control of drug activity (as seen in the delivery of antibiotics and anticancer drugs). Table 1 shows the disadvantages of conventional therapies for age-related diseases in different organ systems.

Table 1 Disadvantages of conventional therapies for age-related diseases in different organ systems

System	Disease	Conventional therapy	Limitations	Ref.
Central nervous system	Alzheimer's disease	Small molecule therapies such as anticholinesterase inhibitors and anti-glutaminergic agents	Peripheral degradation, transport across the BBB limited, high dosage due to low bioavailability and side effects	35–37
	Parkinson's disease	Small molecule therapies such as levodopa, dopamine agonists, COMT inhibitors	Transport across the BBB, uncontrolled on/off cycle, reduced effect with disease progression, side effects such as motor dyskinesis	26
Cardiovascular system	Atherosclerosis	Small molecule therapy such as statin to reduce cholesterol deposition and anti-platelet therapy to reduce platelet accumulation	Low efficiency, side effects, and bleeding risks for anti-platelet therapy	38
		Surgical interventions such as coronary artery bypass grafting and percutaneous coronary intervention	Invasive procedure, restenosis, longer recovery time, patient mortality	38
Immune system	Weakened immune response	Antibiotic therapy and vaccination for fighting infections	High dosage, inefficient killing, reduced immunization in elderly	39
		Chemotherapy, radiotherapy, surgical removal of tumor for cancer	Lateral damage, organ failure, high morbidity, patient mortality	40
		Anti-inflammatory agents and antioxidants for chronic inflammation	Low efficiency, non-specific action, high dosage requirements	41 and 42
Musculo-skeletal system	Osteoporosis	Small molecule therapy such as anti-resorptive therapy	Atypical femur fracture, multiple side effects, jaw-bone osteonecrosis	29
	Osteoarthritis	Small molecule therapy and stem cell therapy	Low efficiency, short life, and accumulation at the joints	43

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With the advent of nanotechnology, many of these challenges have been overcome. Functional nanomaterials (FNMs) can act as efficient transport systems to carry small drug molecules across membranes and deliver the therapeutics specifically to the target site while avoiding the off target unwanted effects.⁴⁴ The FNMs offer several advantages, including minimal invasiveness, a reduction in the number of side effects, effective biological barrier crossing, spatio-temporal control over the delivery site, monitoring of disease progression as well as therapeutic effects, and reduced adverse drug reactions caused by polypharmacy in the elderly. One of the key advantages provided by FNMs is that they can be modified to become stimuli-responsive. Stimuli-responsive drug delivery systems are designed to release therapeutic agents in response to specific external or internal stimuli. In addition, light-responsive FNMs offer the advantage of being tailored to specific wavelengths, allowing customization for different applications. This tunability increases the diversity of these nanoparticles in various fields, from bioimaging to phototherapy. However, one of the barriers that hamper the effectiveness of phototherapy is the depth of penetration of light into biological tissues. The depth of penetration in biological tissues depends on several factors, one of the most important being tissue heterogeneity. The tissue's uneven refractive index results in the scattering of incident light upon entry, causing deviation from its initial trajectory and attenuation.⁴⁵ It has been observed that 408 nm visible light can only penetrate 1 mm into the skin, and 633 nm light has a penetration depth of only 6.3 mm, making it evident that the skin significantly restricts the entry of visible light into the depths of the body.⁴⁶

However, light scattering coefficients of skin, subcutaneous tissue, and muscle show a significant decrease in the wavelength range of 400–1700 nm, which is especially pronounced in the 400–700 nm range.⁴⁷ When the wavelength is greater than 700 nm, the light scattering coefficients of these tissues tend to stabilize, which suggests that using light with wavelengths greater than 700 nm can facilitate the penetration of soft tissue to reach deep-seated regions for phototherapy.⁴⁸ Bodily fluids like water and blood are thought to dominate light absorption in tissues, while some other components, such as melanin and fat, also absorb light that penetrates tissues. However, each of these tissue components has a unique spectral distribution; for example, blood primarily absorbs light at wavelengths less than 600 nm. Additionally, water exhibits local absorption peaks at around 970 nm, 1200 nm, and 1450 nm, while showing a local minimum at 808 nm.^49,50 Due to these special tissue optical properties, absorption and scattering of light can be minimized within some specific windows.⁵¹ Currently, there are confirmed biological transparency windows, including the first window from 700 nm to 950 nm (NIR-I), the second window covering the region from 1000 to 1350 nm (NIR-II), and the third window from 1550 to 1870 nm (NIR-III).⁵² Within these windows, light can penetrate several centimetres of tissue, which is beneficial for achieving phototherapy for bone repair by allowing light to penetrate soft tissue.⁵³ NIR responsive nanoparticles promote higher tissue penetrance⁵⁴ which means they can be used to target organ systems protected by superficial tissue layers. Upon photoexcitation, these light-responsive functional nanomaterials are capable of producing photothermal heat via non-radiative decay and/or reactive oxygen species (ROS) via radiative decay pathways.⁵⁵ Here the evolved heat can be used for precise tumor ablation, pathogen elimination, and even targeted immune modulation. With respect to temperature, there are several modes of hyperthermia including long-term low-temperature hyperthermia (40–41 °C for 6–72 h), moderate-temperature hyperthermia (42–45 °C for 15–60 min), and thermal ablation or high-temperature hyperthermia (>50 °C for >4–6 min).⁵⁶ There is a plethora of parameters that can be manipulated to control the generation of high temperatures including the irradiation conditions (wavelength of irradiated light used, duration of light exposure, power density of irradiation), concentration of nanomaterials, specific absorbance coefficient and choice of nanomaterials.^57,58 As far as the temperature requirement for hyperthermia is concerned, a temperature of 42 °C to 45 °C for periods of 30 to 60 min is required to cause irreversible cellular damage. As the tissue temperature reaches 50 °C, denaturation of protein begins, and the time required to achieve irreversible cellular damage decreases exponentially leading to cell death. Alternatively, the photodynamic ROS generation can be used to kill cells and potentially tackle age-related chronic inflammation (inflammaging).⁵⁹ Functional nanomaterials can also be equipped with nanoreactors that can be used to generate other radicals such as nitric oxide (NO),⁶⁰ and peroxynitrite (ONOO⁻),⁶¹ as well as carbon monoxide (CO),⁶² which are known to be utilized for their anti-inflammatory activity. This also addresses the problem of inflammaging that is prevalent in the older population.⁶³ All the aforementioned strategies can be used to impart therapeutic potential to nanomaterials against various diseases.⁶⁴ In the subsequent sections, deeper insights are provided on how light-responsive FNMs are used in different ways to treat age-related disorders. The typically employed wavelengths of near-infrared (NIR) light can stimulate multiple chromophore centres.⁶⁵ NIR light has been extensively used to activate FNMs to mediate photothermal heat generation,⁶⁶ ROS generation,⁵⁹ photoacoustic imaging,⁶⁷ and fluorescence imaging modalities.⁶⁸ Among the vast ocean of available nanomaterials, one of the frontrunners includes organic nanomaterials which can be derived from organic sources. They can offer a biocompatible approach for treating age-related diseases. These include carbon-based nanomaterials, which range from fullerenes to nanotubes and provide tuneable surfaces. These materials can show several benefits in drug delivery. Another class of nanomaterials in organic nanomaterials include polymeric nanomaterials which are used as versatile carriers, carrying therapeutics directly to diseased cells and with the potential to exhibit stimuli-responsive release. Apart from this, inorganic nanomaterials have also emerged as a major class of FNMs. These inorganic nanomaterials exhibit inherent stability, stimuli responsiveness, as well as several other properties such as upconversion, ion chelation, cell stimulation, etc.

These nanomaterials include plasmonic nanomaterials, which have been used in the therapy of age-related diseases by harnessing the unique interaction between light and their structure. Another class of inorganic nanomaterials include 2D nanomaterials which have a large surface area and possess unique chemical tunability for precisely designed interfaces, enhancing their interaction with targets in age-related diseases. Upconversion nanoparticles follow this trend by converting low-energy light to higher energy light, offering unique tools for therapy in age-related diseases. Transition metal oxides and dichalcogenides are next in line for treating age-related diseases as the metals and chalcogens can be manipulated according to use and they also offer a stimuli-responsive effect that can be beneficial against age-related diseases. Fig. 2 presents an overview of different types of organic and inorganic nanomaterials used against age-related diseases.

Fig. 2 Overview of organic and inorganic nanomaterials used against age-related diseases. Created from Biorender.com.

3. Light responsive functional nanomaterials against age-related diseases

3.1. Organic nanomaterials

Organic nanomaterials are a class of materials with size on the nanoscale (1–100 nm) which can be formed from the compounds containing carbon. These include materials ranging from graphene containing majorly carbon atoms to some of the complex biomolecules like carbohydrates, proteins, and lipids. This organic origin makes them inherently biocompatible, decreasing the toxicity in the body compared to some inorganic nanomaterials. One of the most fascinating properties of organic nanomaterials is their ability to self-assemble. These materials can be used as targeted drug delivery vehicles or as biosensors for disease detection. Organic nanomaterials offer a versatile and promising platform for advancements in nanotechnology. In this review, this class of nanomaterials have been divided into 3 different subclasses: lipid-based nanomaterials, carbon-based nanomaterials and polymeric nanomaterials. Let us discuss these mentioned classes of nanomaterials and how they are aiding in tackling the age-related diseases in detail.

3.1.1. Lipid-based nanomaterials. Liposomes have come out as the safest candidate when it comes to nanocarriers in terms of their biocompatibility.⁶⁹ These are micron to nano-sized spheres composed of natural fatty acids and mimic the structure of the cell membrane. They are also able to encapsulate both hydrophilic and hydrophobic drugs which has allowed their widespread use for drug delivery.⁷⁰ However, their lower rate of accumulation at the target site and passive drug release have limited their therapeutic efficacy. This can be overcome by pairing them with a stimuli-responsive mechanism for drug release, such as light-mediated disassembly resulting in the release of the drug at the target site. This disruption in their structure is reversible which opens the possibility of repeated cycles and controlled intensity of drug release. This is extremely useful for managing age-related disorders due to the varied nature of treatments.⁷¹

In the war with age-related disorders, liposomal formulations have been used against neurodegenerative diseases. For instance, brain targeted liposomes (BTLs) were demonstrated by decorating with transferrin which helped to improve targeting through overexpressed transferrin receptors on the BBB in Parkinson's disease.⁷² These BTLs were loaded with a monoclonal antibody (mAb) SynO₄ that inhibits α-synuclein (AS) aggregation. BTLs below 100 nm were able to cross the BBB and were taken up by primary neurons where SynO₄ was released from nanoparticles. This release led to the binding of SynO₄ to the target receptors resulting in decreased protein aggregation and enhanced neuronal viability. In vivo results showed improved behavioral motor function and learning abilities in mice, offering a great nano-platform for drug delivery against Parkinson's disease. In another example, complex liposomes modified with leptin to cross the BBB were prepared to rescue the degenerated dopaminergic neurons.⁷³ These liposomes were used as a drug carrier for resveratrol (RES) and epigallocatechin gallate (EGCG) against Parkinson's disease. The activity of drugs against neurotoxicity was investigated in vitro in MPTP treated SH-SY5Y cells. The modified liposomes showed an enhanced ability to cross the BBB and enhanced cell viability and target efficiency. Further, these results showed that the conjugation of leptin with liposomes enabled the docking of human brain microvascular endothelial cells (HBMECs) and SH-SY5Y cells via Lep receptors and enhanced their ability to permeate the BBB and cellular uptake. It was also revealed that RES and EGCG encapsulated into liposomes could be a neural defensive strategy by reducing the pro-apoptotic proteins and α-synuclein, and enhancing the anti-apoptotic proteins and the dopamine transporter.⁷⁴ Another study involved the use of liposomes for delivery of Aphanamixis polystachya leaf extract against neurodegenerative diseases. GC-MS data showed that the major constituents of Aphanamixis polystachya leaf extract are 2-pentanone, different acids (octadec-9-enoic acid, 5-hydroxypipeloic acid, etc.), beta-elemene, etc. In vivo results showed a significant improvement in the memory function, locomotor activity and ambulatory performance of dementia induced mice. In addition, a lipid nanocarrier modified with folic acid (FA) moieties was also developed to target activated macrophages for treating rheumatoid arthritis (an inflammatory disorder) with plasmonic gold nanorods (AuNRs), dexamethasone (DEX) and a decoy oligodeoxynucleotide (ODN) to inhibit inflammation. They encapsulated Au NRs which could absorb near infrared light, DEX (common drug for RA) and ODN (to interfere with the pro-inflammatory cascade activated in macrophages by NF-κB) inside the lipid carriers. Along with photothermal therapy (PTT) generated by Au NRs, these therapeutics controlled the inflammation and reduced the swelling and redness in mouse models of RA. The group treated with the entire system and then irradiated with NIR light showed the lowest arthritis scores compared to other groups that were treated with individual drugs themselves.⁷⁵ These liposomal nanoparticles can also be synthesized to show a thermosensitive nature, releasing their payload on temperature rise. Thrombosis caused by the rupture of atherosclerotic plaques presents an example of employing such nanoparticles that can release fibrinolytic plasminogen activators (Pas) like urokinase (uPA) spatiotemporally using light. This has been achieved by a liposomal platform synthesized as a hybrid formulation of Au NRs along with thermosensitive phospholipid dipalmitoyl phosphatidylcholine (DPPC) and a non-ionic surfactant (Brij 58) as shown in Fig. 3.⁷⁶

Fig. 3 Graphical abstract showing the combined thrombolytic impact caused by the liposomal carrier loaded with gold nanorods and urokinase.⁷⁶ Copyright 2021 Elsevier.

The liposomal carrier allows the loading of both Au NRs as the light-responsive agent and urokinase protein as the thrombolytic agent. The Au NRs show plasmonic photothermal response upon NIR irradiation while Brij58 acts as a channeling agent to create nanopores upon heating (melting point = 38–39 °C), thus leading to the release of urokinase in a stimuli-responsive manner at the clot site. This liposomal hybrid achieved thrombolysis in vitro in a halo shaped clot model derived from freshly collected blood from healthy volunteers. Although not demonstrated yet, such nanoplatforms once conjugated with targeting ligands can be used for site-specific controlled thrombolysis preventing off-site bleeding which remains a major concern and adverse effect of fibrinolytic therapies in atherosclerosis management. The excellent biocompatibility of liposomes makes their use ideal for deep-seated issues such as atherosclerotic plaques that rupture and lead to thrombosis. However, it is well known that the majority of liposomal formulations are composed of synthetic lipids and they tend to disintegrate in the bloodstream owing to their poor stability. To overcome these limitations, biological materials, such as erythrocytes, have been given significant attention. To this end, a theranostic nanoconstruct system derived from erythrocytes doped with the FDA-approved NIR imaging agent, indocyanine green (ICG), and surface-functionalized with tPA was developed. Using an in vitro clot model, the dual functionality of these nanoconstructs was tested for NIR fluorescence imaging and clot lysis. These biomimetic theranostic nanoconstructs may provide an ultimate hope for the clinical translation, and can be effectively used in imaging and treatment of blood clots involved in ischemic stroke.⁷⁷

3.1.2. Carbon-based nanomaterials. Carbon-based nanomaterials cover a diverse group of materials derived from carbon or carbon precursors, which exhibit unique properties and functionalities due to their exceptional mechanical, electrical, thermal, and optical properties. Carbon-based nanomaterials are primarily composed of carbon atoms arranged in various structural configurations, including zero-dimensional (0D), one-dimensional (1D), two-dimensional (2D), and three-dimensional (3D) architectures. These nanomaterials show a wide range of diversity in structure, each with unique properties and applications.⁷⁸ Examples of carbon-based nanomaterials include fullerenes, carbon nanotubes, graphene, carbon nanofibers, and carbon nanoparticles. Fullerenes are spherical carbon molecules composed of sp² hybridized carbon atoms, while carbon nanotubes are cylindrical structures formed by rolling up graphene sheets. Graphene consists of a single layer of carbon atoms arranged in a hexagonal lattice, whereas carbon nanofibers are elongated structures with a fibrous morphology. These materials exhibit high mechanical strength, exceptional electrical conductivity, superior thermal stability, and large specific surface areas. Additionally, upon hybridization with different materials, carbon-based nanomaterials can display special optical, magnetic, and chemical properties, making them highly versatile for various applications. Carbon-based nanomaterials can be synthesized through a variety of methods, including chemical vapor deposition, arc discharge, laser ablation, chemical reduction, and template-assisted synthesis. Carbon-based nanomaterials have been used in several applications, including electronics, energy, materials science, medicine, environmental remediation, and catalysis. In the field of medicine, they can be used for drug delivery, imaging, tissue engineering, and biosensing.⁷⁹ Carbon-based materials have increasingly been employed to utilize the advantage of light-driven nanotherapeutics in the context of age-related disorders. A classic example among these is that of carbon dots that have been widely employed against the pathology of Alzheimer's disease.^80–83 In one of these cases, the excellent photophysical stability of carbon dots (CDs) was utilized to denature amyloid beta (Aβ) aggregates and inhibit their formation.⁸¹ When functionalized with DNA aptamers, these CDs were able to bind specifically to Aβ peptides. Interestingly, these CDs were tuned to absorb red light which could offer higher penetration power as compared to the conventional UV light absorbed by CDs. Upon irradiation with a 617 nm LED (10 mW cm⁻²), Apta@CDs generated ROS species which resulted in the loss of toxicity of Aβ peptides while protecting neural cells from cell death. This effect was highlighted in vivo after stereotaxic injection of Apta@CDs which reduced the number of aggregates in coronal brain sections in highly localized brain regions with high Aβ burden through fluorescence enabled therapy. These particles not only allowed deeper penetration of light into tissues of the brain, but also ensured spatiotemporal control to locally abolish the Aβ aggregates. The versatility of carbon dots has also been employed in the case of atherosclerotic foam cells after functionalization with the peptide CLIKKPF (pep-CDs), which interacts with phosphatidylserine (PS) in the membrane of foam cells.⁸⁴ The pep-CDs showcased both fluorescence absorption and photoacoustic conversion post UV irradiation, thus enabling a dual-imaging system. The pep-CDs demonstrated antioxidant, ROS-scavenging, and superoxide dismutase (SOD)-like activities in macrophages. This activity resulted in the inhibition of foam cell formation both in vitro and in vivo at the areas of the atherosclerotic plaques, which could be specifically guided using imaging. Additionally, the targeting ability of pep-CDs allowed for monitoring of the progression of the atherosclerotic lesions, where more plaques would indicate higher uptake and higher PA/FL signals. Similar to carbon dots, fullerenes (C₆₀) have also been used against Alzheimer's disease.⁸⁵ These C₆₀ particles have been utilized specifically for their dual function of ROS generation under irradiation and ROS scavenging in the dark as shown in Fig. 4. When paired with upconversion nanoparticles (UCNPs) and an Aβ targeting peptide KLVFF, the C₆₀ particles were able to localize specifically to the aggregates in the AD model of Caenorhabditis elegans (CL2006) and under NIR irradiation caused the photooxygenation of Aβ and prevented 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) aggregation while also mitigating cytotoxicity. Additionally, in the dark conditions, these particles were able to reduce oxidative stress conditions prevalent in Alzheimer's disease, thereby extending the longevity of the C. elegans worms. While carbon-based materials can act as photo-responsive agents alone, they can also be utilized with other agents to perform dual therapies. For instance, in the case of atherosclerosis, the inflammation driving macrophages have been targeted using chitosan-coated carbon nanocages (CS-CNCs) that can act as both PTT agents and carriers for the PDT agent chlorin e6 (Ce6).⁸⁶ These CS-CNCs were linked to dextran sulphate allowing recognition and uptake specific to the activated macrophages in atherosclerotic plaques through the scavenger type-A receptors (SR-A). Upon 808 nm laser irradiation, the CS-CNCs enabled thermal ablation of the macrophages while also increasing the release of Ce6 which could then be irradiated with 632 nm light to enable ROS-mediated apoptosis. The targeted clearance of these macrophages reduced the pro-inflammatory secretions, smooth muscle cell migration into the atherosclerotic plaques, and finally the eventual area of the plaques. The same PTT/PDT efficacy was also demonstrated in ApoE−/− mice at the carotid arteries after intravenous injection with the particles. The NIR fluorescence from Ce6 allowed for site-specific tracking of nanoparticle accumulation and treatment of atherosclerosis in vivo.

Fig. 4 UCNP@C₆₀-pep inhibited Aβ aggregation in vivo and attenuated the oxidative stress to prolong the lifespan of the CL2006 strain. UCNP@C₆₀-pep produced ROS under NIR to disturb Aβ aggregation and scavenged the overproduced ROS in the dark. As a result, UCNP@C₆₀-pep could ameliorate Aβ-triggered paralysis in CL2006 worms. Reproduced and adapted with permission.⁸⁶ Copyright 2018 Wiley.

These carbon-based materials hence present exciting avenues to age-related disorder treatments with their tunable light-responsive properties, ability to act as carriers, the dual modalities of ROS generation, and scavenging along with excellent biocompatibility profiles. While carbon-based nanomaterials have unmatched impacts on the therapy of age-related diseases, concerns regarding their biocompatibility, specifically in the case of carbon nanotubes, limit their therapeutic applications.

3.1.3. Polymeric nanomaterials. Polymeric nanomaterials consist of polymer chains or networks with at least one dimension in the nanometre scale range, typically ranging from 1 to 100 nm. These materials can be composed of natural or synthetic polymers, and have been explored as an alternative for targeted drug delivery in age-related diseases due to their ability of controlled release of therapeutic molecules, ease of functionalization, versatility and high stability. Examples include biopolymers (e.g., proteins, DNA, polysaccharides) and synthetic polymers (e.g., polyethylene, polystyrene, polyvinyl chloride). Polymeric nanomaterials exhibit unique properties due to their size and the inherent properties of the polymer matrix. These properties may include high surface area-to-volume ratio, improved mechanical strength, enhanced optical and electronic properties, and responsiveness to external stimuli (e.g., temperature, pH, light). Additionally, polymeric nanomaterials can exhibit novel behaviours such as quantum confinement effects, size-dependent reactivity, and altered thermal and mechanical properties compared to their respective monomers. Polymeric nanomaterials have found applications across a wide range of fields, including biomedicine, electronics, energy, environmental remediation, and coatings.⁸⁷ Polymeric nanomaterials are synthesized through various methods, including bottom-up approaches such as nanoprecipitation, emulsion polymerization, and self-assembly, as well as top-down techniques such as nanolithography, electrospinning, and template synthesis.⁸⁸ In the field of medicine, they are utilized for drug delivery, tissue engineering, imaging and diagnostics. In the context of age-related diseases, such as Alzheimer's, cardiovascular diseases, and osteoporosis, polymeric nanomaterials present interesting paths for therapy and diagnosis. For instance, in targeted drug delivery, polymeric nanoparticles can encapsulate therapeutic agents and navigate through biological barriers to reach specific sites of pathology in age-related diseases. Their tuneable surface properties enable functionalization with targeting ligands, facilitating selective uptake by diseased cells while minimizing off-target effects and enhancing therapeutic efficacy. By combining diagnostic and therapeutic functionalities into multifunctional platforms, polymeric nanomaterials can have potential to offer theranostic interventions. One of the major challenges with therapeutic modalities for neurodegenerative diseases is the blood brain barrier (BBB) which protects the brain from foreign particles/pathogens.

To this end, several strategies have been devised to bypass the BBB and deliver the nanoparticles/drug molecules for maximum utilization of therapeutic modalities including the use of targeting peptides against biomarkers. For example, a versatile polymer-dispersed liquid crystal (PDLC) nanoparticle functionalized with the LPFFD (leucine–proline–phenylalanine–phenylalanine–aspartic acid) peptide is designed with high Aβ-binding affinity, NIR-responsive drug release, and photothermal degradation properties for efficient disassembly of Aβ (Fig. 5).⁸⁹ A photothermal hydrophobic core made of conjugated PDPP3T-O14 polymer was used which shows strong NIR absorption. The 5-mer β sheet breaker peptide LPFFD was conjugated to specifically target Aβ. Using curcumin as an additional inhibitor of Aβ aggregation, this nanoparticle system succeeded in dramatically lowering the Aβ aggregation induced cytotoxicity in PC12 neuronal cells. Such targeting strategies that address the blood–brain barrier's selectivity are of huge importance, as they can enhance therapeutic effects on the brain, potentially decreasing the advancement of age-related neurodegenerative diseases and enhancing overall treatment outcomes. With the advancing age, just like Alzheimer's disease the aggregation and accumulation of misfolded proteins (α-synuclein) results in the pathogenesis of Parkinson's disease. Towards this end, polydopamine-based NIR photothermal-assisted magnesium oxide-based nanoparticles (MgOp@PPLP) were used as neuroprotectants, gene transfection agents, and photothermal agents. An SH-SY5Y in vitro model induced by rotenone was used to show the suppression of α-synuclein levels and the reduction of inflammation. The nanoparticles were injected into MPTP-induced Parkinson's mouse models leading to restoration of Nissl granules, reduction of brain inflammation, and decrease in TH+ neuronal loss.⁹⁰ Synergistic approaches using different treatment modalities in a single platform have been used extensively to tackle neurodegenerative diseases.

Fig. 5 Schematic illustration of PDLC NPs for chemo-photothermal treatment for Aβ aggregation. (A) Chemical structures and the synthesis of PDLC NPs. (B) Schematic illustration of PDLC NP-mediated chemo-photothermal treatment by combining NIR light-tunable drug release and photodegradation of amyloid β. Reproduced with permission.⁸⁹ Copyright 2021 Wiley-VCH.

For instance, lipid-coated polydopamine nanoparticles (L-PDNPs) have been proposed as antioxidants, neuroprotective agents, and photothermal agents against Parkinson's disease.⁹¹ The L-PDNPs were designed to act as a photothermal conversion platform to increase the intracellular temperature to produce a Ca²⁺ influx in SH-SH5Y models. Upon NIR stimulation of treated cells, a constant increment in temperature (up to 34 °C) and Ca²⁺ ions was observed along with a subsequent decrease in ROS levels. With the irradiation of an 808 nm laser, L-PDNPs showed a concentration dependent increase in temperature generation with a positive correlation. The temperature increase showed 15 °C at 0.1 mg mL⁻¹, 20 °C at 0.25 mg mL⁻¹ and 35 °C at 5 mg mL⁻¹. The L-PDNPs also showed an increment in output temperature with the increase in the power density of the 808 nm laser with the maximum reaching up to 8 °C. In another example, PEGylated polydopamine coated gold nanoparticles with specific binding to the thermosensitive ion channel were developed as nano-transducers for NIR-II window photo-stimulation of neurons in rats.⁹² The nanoparticles were functionalized with an anti-TRPV1 antibody for targeting and exhibiting photothermal performance to activate the Ca²⁺ influx of neurons in vitro. The use of these nanoparticles helps in the NIR-II window in achieving a non-invasive photothermal stimulation of neurons in living rats, inducing excitation of neurons as deep as 5 mm beneath the cortex. As the immune system deteriorates, infections like UTI (urinary tract infection) also become more frequent with age, especially in women. Towards this end, a biomimetic core–shell low temperature photothermal antibiotic nanoplatform against UPEC (uropathogenic Escherichia coli) was developed.⁹³ The polydopamine core imparts photothermal property while the biphenyl mannoside shell shows multivalent high-affinity to UPEC leading to an ultra-strong binding of nanoparticles towards UPEC. Under 808 nm laser irradiation, the nanosystem showed an increase in temperature with the increase in power density with a temperature rise of around 30 °C at 1.5 W cm⁻². Similarly, a controlled increase in temperature was observed with the increase in the concentration of nanoparticles. The nanoparticles showed a low temperature photothermal bactericidal effect (∼48 °C) and eliminated almost 100% bacteria in a mouse-based UTI model. Consequently, the high photothermal energy of the nanoparticles appears to be destructive in the affected bacterial area, while the overall environment remains at a low temperature. In addition to eradicating infectious agents, polymer-based NPs have also been used to activate the immune system. This sort of immunomodulation has been used to stimulate the immune cells against cancer. An approach for immunomodulation is shown by semiconducting polymer nano-enzyme (SPNK) particles made of the semiconducting polymer poly(cyclopentadithiophene-alt-benzothiadiazole) (PCB), and linked with an immune activating enzyme KYNase through a singlet oxygen responsive linker.⁹⁴ These SPNKs accumulate at tumor sites and upon 808 nm NIR excitation generate singlet oxygen radicals to release KYNase. The KYNase enzyme reverses Kyn induced T cell suppression that mediates increased proliferation and infiltration of effector T cells at tumor sites.

Inflammation is also modulated using polymer based FNMs. Since cytokines are the major mediators of cellular communication and play a pivotal role in inflammation regulation (especially in the elderly), anti-cytokine therapy against pro-inflammatory cytokines is one of the preferred choices of treatment that can be utilized against inflammation. For instance, multifunctional alveolar macrophage like nanoparticles with photothermal inactivation property have been used against SARS-COV-2 infection.⁹⁵ The nanoparticles were designed to be administered through atomization inhalation followed by NIR irradiation of the respiratory tract. Poly(lactic-co-glycolic acid) (PLGA) cores were coated with alveolar membranes and doped with an NIR activable photothermal agent 2PTE-2NDTA. The nanoparticle system was able to absorb a variety of proinflammatory cytokines through the various cytokine receptors (IL-6 and IFN-γ) present on the coated nanoparticles and upon NIR light irradiation, photothermal based antiviral activity of the nanoparticles was switched on. Another important disorder with an inflammation-based pathology is osteoarthritis. It is one of the most prevalent inflammatory diseases arising from the risk factors of older age, characterized by articular degeneration.^96,97 Several risk factors lead to age-related changes in the joints such as chondrocyte senescence, increased oxidative damage, and reduced matrix synthesis and repair. These changes arise due to increased expression of cytokines and matrix degradation enzymes. The current pharmacological therapies target matrix degradation, inflammatory processes, pain, or bone turnover.⁹⁸ These therapies are constrained by limited accumulation and short life at the affected joint sites, multiple dosing, and numerous unwanted side effects. NIR-responsive nanomaterials have been used for deeper tissue penetration and site-specific controlled anti-inflammatory therapies for osteoarthritis (OA). One recent study utilized the anti-inflammatory effect of nitric oxide (NO) by pairing haemoglobin (Hb) bound NO as a NIR-responsive nanogenerator.⁹⁹ The authors also paired a Notch-1 siRNA to the Hb for RNA interference of Notch-1 signalling necessary for immune cell proliferation and used PLGA–PEG nanoparticles to carry the cargo. In this nano-construct, Hb acted as a photothermal agent creating local hyperthermia enough to break S–NO bonds and release nitric oxide upon 650 nm laser exposure. The siRNA was electrostatically bound to Hb and an amphiphilic coating with a poly[lactic-co-glycolic acid] (PLGA) core and a polyethylene glycol (PEG) shell increased cellular uptake and RNAi efficiency. The photothermal heat showed a synergistic effect with the nanoparticles with a reduction in the levels of cytokines like TNF-α, IL-1β, IL-6, COX-2, and IL-8 in vitro. Additionally, there was an increased accumulation of these NPs at the joints in papain-induced OA mouse models owing to Notch-1-siRNA specificity to OA. In vivo, the OA progression was slowed down due to a decrease in synovial inflammation and cartilage erosion. Another study used ROS scavenging along with a drug delivery system by coating melanin loaded into the Pluronic F127 micellar core with polydopamine (PDA) to form DHMP/M nanoparticles.¹⁰⁰ These nanoparticles were responsive to both ROS and NIR (808 nm) due to the presence of melanin and PDA shell respectively. The study demonstrated that in a ROS-abundant environment of osteoarthritic knees, the PDA shell is slowly oxidized and broken enabling a controlled long-term release of loaded drugs, while exogenous NIR laser irradiation can cause a short burst and a faster release of the loaded cargo, making the construct ideal for personalized therapy post-intra-articular administration. Additionally, the release of melanin from the nanoparticles caused ROS scavenging both in vitro in chondrocyte cultures and in vivo in an OA mouse model. The PTT effect was synergistic with ROS scavenging of melanin to reduce OA progression via an effect on the toll-like receptor/protein kinase-B (TLR-2/Akt) axis. All these examples highlight how several strategies involving the pairing of light with nanomaterials can allow modulation of different aspects of the immune system to counter many age-related problems like infections, wound healing and osteoarthritis. While organic nanomaterials offer biocompatibility and self-assembly advantages, the diverse world of inorganic nanomaterials presents a broader spectrum of properties for age-related disease management. Inorganic materials, like plasmonic nanomaterials and upconversion nanomaterials, exhibit additional properties like tuneability in the therapeutic properties including plasmonic effects, the upconversion phenomenon and material associated photothermal and photodynamic therapeutic effects.

3.2. Inorganic nanomaterials

Inorganic nanomaterials are structured with inorganic metals such as transition metals, plasmonic metals, lanthanides, etc. Unlike organic nanomaterials, these materials are robust and can withstand harsh environments and maintain their precise structure. Some of these nanomaterials show plasmonic effects, interacting with light in unique ways to enhance the killing of diseased cells. Others possess the remarkable ability to convert low-energy light into higher-energy light, enabling deeper tissue penetration for diagnostics and therapy. Still others boast a dynamic combination of properties, acting as magnetic hyperthermia mediators or efficient conductors. This unique blend of functionalities allows scientists to tailor these nanomaterials for various applications. They can be designed to target specific molecules within cells, act as heat generators for precise cell destruction, or even illuminate biomarkers for early disease detection. In essence, inorganic nanomaterials offer a versatile and powerful platform for advancements in healthcare, particularly in the fight against age-related diseases.

3.2.1. Plasmonic nanomaterials. Plasmonic nanoparticles are an interesting class of nanomaterials that are typically composed of noble metals such as gold, silver or platinum. Plasmonic nanoparticles are characterized by a phenomenon known as localized surface plasmon resonance (LSPR) which refers to the confinement of plasmonic excitations to the surface of individual nanoparticles. This phenomenon results in strong electromagnetic field enhancements localized around the nanoparticle. This phenomenon occurs at specific wavelengths depending on the size, shape, and material composition of the nanoparticles, making them useful for enhancing various optical processes such as surface-enhanced Raman scattering (SERS), fluorescence enhancement, and photothermal therapy. Due to their unique optical, electronic, and chemical properties, ease of functionalization and biocompatibility, gold nanomaterials find applications across various fields ranging from sensing, electronics, chemical catalysis to environmental remediation. For practical applications of plasmonic nanomaterials, precise control over their size, shape, composition, and surface properties is essential. This requires robust and scalable synthesis methods which include chemical reduction methods, seed-mediated growth method, template-assisted synthesis, electrochemical synthesis and green synthesis methods. Due to their ability to manipulate light at nanoscale through SPR, plasmonic nanomaterials have emerged as powerful tools in the field of medicine and diagnostics. The biomedical applications of these nanoparticles encompass biomedical imaging, drug delivery, cancer therapy, biosensing and theranostics.¹⁰¹ The usage of plasmonic nanomaterials for therapy of various diseases is being practised from a long time. Amongst the plethora of diseases where plasmonic nanomaterials have been used to cure or diagnose, age-related diseases are some of the most common diseases. Plasmonic nanomaterials usually can be used in several ways for addressing the age-related diseases including delivery of drug molecules or photosensitizers, photo mediated therapies and mechanically hindering the progression of diseases.

Traditional therapy of atherosclerosis focuses on reduction of cholesterol deposits and platelet accumulation and on lumen dilation using angioplasty or coronary artery bypass grafting. Cholesterol-lowering statin therapies are challenged by limited reductions in plaque deposits and a wide array of side effects. The invasive procedures for revascularization like percutaneous coronary intervention (PCI) are challenged by restenosis, and preventative dual anti-platelet therapy increases bleeding risks. Meanwhile, surgical options like coronary artery bypass grafting face concerns of longer recovery times, and patient mortality and morbidity risks.¹⁰² The use of photothermal treatments for the ablation of plaques and fibrin deposits presents an excellent non-invasive option to overcome many of the traditional treatment limitations. For example, through plasmonic photothermal therapy (PPTT) using gold coated sub-micrometer sized silica particles, significant atheroma volume reductions post laser irradiation have been achieved for over a period of 6 months (ΔV = −7.54% at baseline and/−22.92% after 6 months) in the Yucatan miniature swine.¹⁰³ This was followed up as a clinical trial of plasmonic nano-photothermal therapy of atherosclerosis that delivered the same particles using two cardiac catheterization strategies: (1) nanoparticles on a bioengineered “on-artery” patch and (2) nanoparticles delivered through targeted stem cells or microbubbles, and compared their pathological markers with stenting controls.¹⁰⁴ At 12 months of follow-up, the total atheroma volume and the total plaque burden reduced more as compared to stenting controls while the arterial remodelling/restenosis levels remained lower, proving PPTT to be an excellent alternative to stenting using minimally invasive catheterization. Although this modality proves to be promising, the plaques that get ruptured become new hotspots for thrombus formation composed of insoluble fibrils and the traditional fibrinolytic therapy utilizes the natural anti-clotting mechanisms of the body. This increases the risks of haemorrhage-based complications that can be fatal and require highly precise dosing. To overcome this, certain strategies using PTT have been developed for fibrinolysis. One of the studies in the concerned area showed gold nanorods (GNRs) conjugated with anti-fibrin antibodies that could photothermally ablate blood clots in vitro and in vivo in the blood vessels of mice. These GNRs showed a temperature increase of 10 °C when the concentration of nanorods was increased twice. They also showed that GNRs conjugated to streptokinase, a traditional therapeutic drug, could reduce the required dose significantly below therapeutic doses leading to risk aversion.¹⁰⁵

Another clinical concern which arises due to accumulation of biomolecules is the age-related neurodegenerative diseases. Conventional therapies for age-related neurodegenerative diseases primarily focus on symptom management and slowing down the disease progression. These include small drug molecules, monoclonal antibodies, gene therapies, and stem cell therapies which have limitations like long-term side effects, immunogenicity, and low precision in targeting. Nanoparticle-based therapy holds promising potential for addressing age-related neurodegenerative diseases offering unique advantages in this context.

For instance, researchers have explored the use of diverse nanomaterials for drug delivery to the brain in neurodegenerative diseases.¹⁰⁶ Among these, the plasmonic nanomaterials have been used up to their extreme potential. Several studies have demonstrated the effectiveness of plasmonic nanoparticle-based photothermal therapy in preclinical models of neurodegenerative diseases. With the aid of optimized heat generation, these not only protect neurons from degeneration but also hold the promise of reducing the senescence-associated factors, assisting in a multidimensional approach for dealing with age-related neurodegenerative challenges. For instance, researchers have developed spherical gold nanoparticles functionalized with specific ligands for beta-amyloid, enabling targeted delivery to amyloid plaques in an Alzheimer's disease model.¹⁰⁷ Upon 532 nm laser irradiation, these nanoparticles induced plasmon-dependent localized hyperthermia, promoting the disaggregation of beta-amyloid and reducing plaque burden. Studies in this field have further demonstrated that NIR light-responsive nanoparticles hold significant promise in addressing these diseases. In one of the studies, pramipexole (a non-ergot dopamine agonist) loaded hollow gold nanospheres were used for the treatment of Parkinson's disease where the nanoparticles were irradiated with an 808 nm laser to perform photothermal therapy attaining a temperature of 50 °C and a higher drug release rate from the nanoparticles. This also led to improved pharmacokinetics, pharmacodynamics, and early recovery in mice.¹⁰⁸ In another study, the authors have reported the use of targeted gold nanoparticle composites against Parkinson's disease where they have investigated the effect of size of nanoparticles for successful therapeutic effects. These nanoparticles have been synthesized via a combination of electrostatic adsorption and photochemical immobilization, and they can carry plasmid DNA against α-synuclein (SNCA gene) and were targeted against the nerve growth factor (NGF) receptor. In vitro results showed that the nanoparticles were internalized by PC12 cells and the pDNA escaped from the lysosome and expressed shRNA which then got associated with the RNA-induced silencing complex (RISC) to suppress SNCA expression via mRNA degradation. In the in vivo studies, the nanoparticles showed potential to cross the blood–brain barrier and inhibited the apoptosis of substantia nigra striatum dopaminergic neurons.¹⁰⁹ Similarly, silver nanoparticles have also been used against neurodegenerative diseases. However, there are controversial data regarding the use of silver nanoparticles due to their ability to ionize after entry into cells, causing the release of silver ions inside the cytoplasm. This leads to increased ROS formation and mitochondrial toxicity leading to apoptosis or necrosis.¹¹⁰ Hence, in order to use these nanoparticles against neurodegenerative diseases, surface functionalization becomes the best probable solution. Silver nanoparticles synthesized via green synthesis methods have shown less toxicity and can be used against neurodegenerative diseases.¹¹¹ One of such studies shows a green synthesis method used for silver nanoparticle preparation and investigation of their preventive effects on brain deficits in a sporadic Alzheimer's rat model. The aqueous extract of N. khasiana leaves was used as a reducing and stabilizing agent in silver nanoparticle preparation. The authors confirmed the coating of leaf extract polyphenols onto the surface of silver nanoparticles with FTIR. Streptozotocin was injected intracerebroventrically to induce a sporadic AD effect in rat models. Finally, with the help of the Barnes maze test and object recognition tests, the authors confirmed the ability of silver nanoparticles to prevent the damage caused due to Alzheimer's disease.¹¹² Similarly, the leaf extract of Mucuna pruriens has also been utilized to synthesize silver nanoparticles. The extract of this plant is known to contain high concentrations for L-dopa which can be a source for the formation of dopamine in patients with Parkinson's disease. In this case, the authors investigated the effect of these nanoparticles on one of the typical conditions of Parkinson's disease, which is the loss of reaction to external stimuli called catalepsy. The results showed that the silver nanoparticles showed potential to counteract catalepsy in 3 month old mice in a dose dependent way.¹¹³ Platinum, another plasmonic metal, has also been explored in the field of neuroprotection. However, the studies have not been conducted against age-related neurodegeneration and also do not take light into consideration. Also, studies show that the size of platinum nanoparticles plays a major role in cytocompatibility, where large size particles cause cell damage in neural cell lines.¹¹⁴ However, studies have also shown that plasmonic nanoparticles act as strong ROS scavengers. A study involving platinum nanoparticles used against ischemic stroke and tissue plasminogen activator related brain damage showed a strong neuroprotective effect in mice. The strong ROS reduction capacity of the platinum nanoparticles has been shown to be accountable for the neuroprotective and neurological effects.¹¹⁵ Another study involving platinum nanoparticles demonstrated the superoxide anion reducing effect leading to improved neuroprotective effects in the mouse ischemic brain.¹¹⁶ Thus, further studies are required to confirm the biocompatibility and usability of platinum nanoparticles against age-related neurodegenerative diseases.

As discussed above, immunosenescence, the gradual deterioration of the immune system with age, poses another critical challenge in combating age-related disorders. Addressing this decline in immune function along with increased inflammation is paramount for developing effective interventions as these changes become characteristic pathologies for various age-related disorders. Since infections are the 3rd biggest cause of death in populations above 65 years,¹¹⁷ it is imperative to look for strategies to defend the elderly against these infections. To this end, plasmonic nano-therapies have been utilized as they harbour the potential to disrupt the cellular components of pathogens causing their death. For instance, surface adaptive gold nanoparticles were functionalized with the integration of both weak and strong electrolyte layers, forming a pH responsive nanoplatform.¹¹⁸ Under physiological conditions (pH 7.4), these nanoparticles dispersed well in healthy tissues, while under negatively charged bacterial surfaces of the MRSA (methicillin resistant Staphylococcus aureus) biofilm (pH 5.5), they showed strong adherence. Also, under pH 5.5, the nanoparticles showed an aggregation dependent shift in the absorption peak and an enhanced absorption in the NIR window. When irradiated with an 808 nm laser in a rabbit model, the gold nanoparticles showed a photothermal rise leading to the elimination of biofilms observed by the decrease in colony forming units. These reports make this strategy a suitable candidate for tackling other pathogens that are prevalent in older populations. Killing of macrophages through PTT has been utilized to drive down inflammation in age-associated diseases like atherosclerosis using nanomaterials like gold. For instance, under 808 nm laser irradiation, the PTT effects of gold nanorods were investigated in macrophage cell line Ana-1 and ApoE knockout mice. Gold nanorods exhibited a significant cell-killing efficacy of macrophages and inflammatory macrophages in femoral artery restenosis at very low concentrations as well as under low NIR powers.¹¹⁹ Wound healing hampered by infections can also cause severe tissue damage leading to potentially fatal complications. One of the studies showed hastened wound healing in cutaneous wounds by photo-biomodulation therapy using 808 nm laser irradiated gold nanoparticles. In another example, gold nanoparticles under 904 nm laser irradiation when paired with hyaluronic acid acted as stimulants for collagen production which helped in wound closure in excisional wound in Wistar rats.¹²⁰ The mechanisms for the acceleration of wound closure involved a reduction in pro-inflammatory cytokines (IFNϒ, IL-1β, TNFα, and IL-6) and oxidative damage and an increment in the levels of the antioxidant glutathione (GSH).

Plasmonic nanoparticles have also been used to target and clear senescent cells where conventional approaches have failed. When paired with conventional medicine, these FNMs can show a synergistic effect. Currently, many anti-senescence drugs have entered the discovery chain, which can either eliminate senescent cells (senolytic) or alter the secretory phenotype (SASP) of senescent cells (senomorphic).¹²¹ Recently, a study showed the clearance of senescent microglia by surface-targeted chiral gold NPs which significantly improved the symptoms of Parkinson's disease in mice as shown in Fig. 6.¹²²

Fig. 6 Illustration of the apoptosis pathways of senescent microglia cells induced by chiral NPs under the irradiation of an 808 nm laser in the brain of PD mice. Reproduced with permission.¹⁰⁴ Copyright 2015 Royal Society of Chemistry.

Upon 808 nm irradiation, these particles were able to activate apoptosis pathways in senescent microglia without any photothermal damage to the healthy cells. However, further studies on use of light mediated plasmonic nanomaterials are needed to confirm the effects on clearance of senescent cells. Plasmonic nanomaterials have been used as invaluable tools for managing age-related diseases. However, their therapeutic applications are limited due to the dependence on low-energy light radiation to keep the FNM therapy safe for the body. Upconversion nanomaterials offer a game-changing approach. These materials possess the remarkable ability to convert low-energy light to higher-energy light which can be used to activate therapeutic agents or directly generate heat within diseased cells. This deeper tissue penetration and targeted therapy holds immense promise for treating age-related diseases.

3.2.2. Upconversion nanomaterials. Upconversion nanomaterials are specialized nanomaterials that exhibit the phenomenon of upconversion luminescence, where they absorb low-energy photons (typically in the near-infrared or infrared range) and emit higher-energy photons (such as visible or ultraviolet light).¹²³ This process involves non-linear optical interactions within the nanomaterials, leading to the conversion of long-wavelength excitation into shorter-wavelength emission. Upconversion nanomaterials use several mechanisms, including energy transfer processes, multiphoton absorption, and excited state transitions, to convert low-energy photons into higher-energy photons. These materials typically consist of rare-earth ions, semiconductor nanocrystals, or organic dyes embedded in a host matrix, which facilitates the upconversion process through controlled energy transfer pathways. These nanomaterials can be synthesized by the hydrothermal/solvothermal method, thermal decomposition method, template-assisted method, ligand-mediated method and chemical vapor deposition method.¹²⁴ Upconversion nanomaterials exhibit tuneable emission properties, which allows great control over the optical properties of the emitted light. Their ability to emit visible or ultraviolet light upon excitation with near-infrared or infrared radiation enables deep tissue imaging with reduced background autofluorescence. Furthermore, upconversion nanomaterials have been utilized after functionalization with targeting ligands or therapeutic agents for targeted drug delivery, photodynamic therapy, and photothermal therapy. In one case, researchers have developed such a system where the UCNPs could induce apoptosis through mitochondrial matrix swelling and help monitor cytochrome C (Cyt C) presence inside the cells. The absorption signal of the UCNPs overlapped with the absorption of Cyt C, which allowed them to monitor its concentration. This becomes relevant as the quantification of Cyt C can be used to study the apoptotic pathway due to mitochondrial ROS.¹²⁵ Various other groups have utilized similar UCNPs which could help selective eradication of cancerous cells. Another interesting study worked upon an upconversion NP that could produce a UV signal through NIR irradiation, which was further absorbed by TiO₂ for PTT. Fig. 7.¹²⁶

Fig. 7 UCNPs absorbing NIR and emitting UV, which gets absorbed by TiO₂ for PTT and PDT. Reproduced with permission.¹²⁶ Copyright 2015 American Chemical Society.

Since cancer becomes more prevalent with age due to a systemic decline in the immune system, UCNPs that can treat as well as help understand the development of disease become an important combat strategy. UCNPs also offer a novel strategy to manage inflammation directly (by reducing infection load) and indirectly (by interrupting pro-inflammatory signals and stimulating anti-inflammatory signals). UCNPs-Ce6–Mn (CO)5Br@Silane is an interesting system developed by Liu and team that could convert NIR to red light, which was absorbed by Ce6 to generate ROS that would break the Mn–CO bond liberating CO and Mn²⁺. Mn²⁺ can degrade H₂O₂ to generate O₂, regenerating the oxygen supply for PDT while the CO molecules manage inflammation due to their noted anti-inflammatory effect. This system was tested against E. coli and S. aureus and it showed a remarkable 80% reduction in bacterial load.¹²⁷ Apart from bacterial infections, yeast infections are also more likely to be observed with progressing age, as more than 50% of incidences of candidiasis are reported in people above 65,¹²⁸ and hence many photo-responsive nanoformulations have been developed to combat it. For instance, a UCNP based nano-system was utilized as a functional nanocarrier to load protoporphyrin IX (PpIX) for NIR mediated PDT.¹²⁹ The PpIX loaded UCNPs were modified with oligo-chitosan to increase the affinity of nanoparticles towards the yeast and hyphal cells. Upon irradiation, the nanoparticles absorb NIR light (808 nm) and emit light in the visible range (540 nm) which in turn excites the PpIX molecules leading to the generation of ROS inhibiting the Candida albicans biofilm formation and destroying the already existing biofilms. Similarly, neuroinflammation was treated by Hu and team, who employed the release of NO using an upconverted UV signal by externally irradiating the selective region with NIR. UCNP was co-loaded with SNAP (a NO donor which releases NO under UV radiation) and Pae (an anti-oxidant traditionally used for its neuroprotective effect) for a synergistic treatment.¹³⁰ Wound healing has also been greatly worked on using UCNPs and has been reviewed by another group, which becomes relevant in the context of battling aging and its related disorders.¹³¹ Upconversion NPs have also been used for anti-aggregation therapies under external light irradiation. A group achieved cholesterol efflux from macrophage foam cells using UCNPs coated with a silica shell and conjugated with Ce6 to form UCNPs@SiO₂-Ce6.¹³² Upon 980 nm laser irradiation, the UCNPs@SiO₂-Ce6 nanosystem produces upconversion emission that further activates the Ce6 photosensitizer (660 nm) to generate ROS for photodynamic therapy. This PDT effect leads to the activation of autophagic pathways resulting in reduced lipid accumulation in the macrophages and eventually reduces the progression of atherosclerosis. Upconverting nanosystems have also been designed for the controlled release of nitric oxide for stimulating osteogenesis.¹³³ This approach exploits the high photoconversion efficiencies of lanthanide UCNPs with a core of NaYF₄:Yb/Tm and two outer shell layers of NaYF₄:Nd/Yb and NaYF₄ respectively to excite the NO donor BNN contained within mesoporous silica NPs functionalized with alendronate for bone targeting. Upon 808 nm irradiation, UCNPs get excited to generate UV/blue light which when absorbed by BNN triggers NO release within a controllable therapeutic window, overcoming the challenge of conventionally short-lived NO delivery in tissues. In OVX mice, the UCNPs-BNN showed much higher bone mass, bone volume, and bone thickness retention as compared to controls. Apart from inducing cell division to combat ageing, UCNPs have also been shown to activate existing cells for treating age-related neurodegeneration. A group utilized UCNPs for cell activation by linking the release of bacterial lipopolysaccharide (LPS) with the upconverted signal. The LPS could activate microglia in the brain under the exact spatial control of NIR radiation. For multiple therapies that require precise control of their duration and therapeutic windows, photosensitized nanomaterials can help overcome short-term failures and longer-term treatment side effects. Upconversion nanomaterials have been worked upon against therapy for age-related diseases by enabling targeted activation of drugs deep within tissues. However, the field of nanomedicine is constantly evolving. 2D nanomaterials present a unique platform for therapeutic interventions. Their atomically thin structure and exceptional surface area allow for efficient drug loading and precise interaction with diseased cells. This opens doors for exploring novel therapeutic strategies, such as targeted drug delivery with controlled release with improved cellular uptake.

3.2.3. Two dimensional nanomaterials. 2D nanomaterials consist of atomically thin sheets of materials that are typically one or a few atoms thick. These materials can be composed of a variety of elements, including carbon (e.g., graphene), transition metals (e.g., transition metal dichalcogenides), boron (e.g., boron nitride), and other layered materials. Each layer is held together by strong covalent or van der Waals bonds, resulting in a flat, planar structure. 2D nanomaterials exhibit a range of unique properties arising from their atomically thin nature and high surface-to-volume ratio. These nanoparticles inhabit properties including high mechanical strength, flexibility, transparency, high electrical conductivity or semiconducting behavior, tuneable band gaps, and extraordinary thermal conductivity.¹³⁴ 2D nanomaterials also possess unique optical properties, such as strong light–matter interactions and quantum confinement effects. Various methods have been developed for the synthesis of 2D nanomaterials, including mechanical exfoliation, chemical vapor deposition, solution-based methods (such as liquid-phase exfoliation and hydrothermal synthesis), and physical vapor deposition. These methods provide control over the thickness, size, shape, and crystallinity of the 2D nanomaterials. Owing to their versatile characteristics, spherical nanoparticles enable precise drug delivery, enhancing the bioavailability of therapeutic agents in the targeted brain regions. However, 2D nanomaterials with properties like higher surface area for functionalization and tunable thickness have been extensively used for drug delivery, biomedical imaging, tissue engineering, biosensing and light-mediated therapies. 2D nanomaterials have been used to tackle age-related diseases, helping in targeted drug delivery and therapy and managing the comorbidities associated with aging.¹³⁵

Working as an essential component for cellular energetics, mitochondria are susceptible to gradual and cumulative damage over time including oxidative stress, impaired mitochondrial dynamics, and compromised bioenergetics. One such example has been demonstrated by using a zeolitic imidazolate framework 8-coated Prussian blue nanocomposite which was loaded with quercetin (ZIF-8@PB@QCT). The nanoparticle system holds the ability to penetrate through the BBB to the site of mitochondrial damage and under NIR irradiation imparts its photothermal effect and quercetin-mediated anti-inflammatory action.¹³⁶ A 2D graphdiyne-based smart dual functional nanoplatform (GDY) endowed with both chemotherapy and photothermal therapy was used against PD. The nanosheets were loaded with minocycline as a neuroprotective agent by π–π stacking. Upon irradiation with a NIR laser, GDY showed a photothermal conversion efficiency of 32% and a release of more than 30% loaded drugs. Upon NIR irradiation, the nanosystem showed an increase of 20 °C as the nanoparticle concentration was doubled.¹³⁷ Another interesting 2D nanoplatform shuttled by black phosphorus was targeted to the brain with the help of lactoferrin and loaded with paeoniflorin as a neuroprotective agent. The nanoplatform showed high biocompatibility, and upon NIR irradiation, a photothermal efficiency of 37% and a payload release of up to 94.9%. Upon 808 nm laser irradiation, the nanoplatform showed a regular increase of temperature with a corresponding increase in the concentration of nanoparticles in vitro. Similarly, with an increase in power density, a regular increment in temperature generation was observed. The nanoplatform showed a dose-dependent increase in cell viability and an improved ability to cross the blood–brain barrier with NIR irradiation both in vitro and in vivo.¹³⁸ Furthermore, WS₂ nanosheets present another class of 2D nanomaterials that have been investigated for their anti-inflammatory and photothermal properties. To this end, a strategy involving chemically exfoliated WS₂ nanosheets helped in efficiently inhibiting the amyloid-β peptide aggregation and enabled NIR irradiation-dependent photothermal treatment of Alzheimer's disease. The amyloid monomers get adsorbed over the surface of nanosheets, which inhibits their aggregation. Additionally, irradiation with a NIR laser (808 nm) helps to dissolve the amyloid aggregates which was further confirmed by circular dichroism of amyloid fibrils after irradiation leading to a 30% decrease in beta fibril secondary structures.¹³⁹ Overall, the synergistic approaches of nanoparticle-based therapy represent a promising frontier in the battle against neurodegenerative diseases. By combining various modalities, each designed to address specific facets of neurodegeneration, researchers have aimed to create synergies that enhance therapeutic efficacy. Whether it is crossing the blood–brain barrier, targeting pathological proteins, or mitigating oxidative stress, the collaborative potential of therapeutic modalities demonstrates a comprehensive approach. In one study, a semi-oxidized tin sulphide nanosheet based CO nanogenerator was utilized to reduce inflammation.¹⁴⁰ Upon irradiation with an 808 nm laser, the tin sulphide nanosheets acted as photothermal agents while reduced levels of pro-inflammatory markers such as TNF-α, IL-6, and IL-1β were observed when irradiated with a 561 nm laser (Fig. 8).

Fig. 8 CO generation via CO₂ photoreduction by the POS (partially oxidised disulphide) moiety in the FNM upon 561 nm laser irradiation to reduce inflammation and generate photothermal heat for tumor ablation. Reproduced with permission.¹⁴⁰ Copyright 2019, American Chemical Society.

Interestingly, it is also possible to activate both innate and adaptive immune systems using light-responsive FNMs. This was demonstrated in a nanoplatform containing Ti₃C₂ MXene paired with ovalbumin (OVA) and Mn²⁺ targeting osteosarcoma.¹⁴¹

The irradiation of this nanoplatform through PTT induced the release of mitochondrial DNA (mt-DNA) along with the release of OVA and Mn²⁺ at the tumor sites. The released mt-DNA and Mn²⁺ induce the activation of the innate immune responses through the cGAS–STING signalling pathway. The cGAS–STING pathway is a component of the innate immune system that functions to detect the presence of cytosolic DNA and, in response, triggers the expression of inflammatory genes that can lead to senescence or to the activation of defense mechanisms. On the other hand, the released OVA along with other tumor antigens enhances the adaptive T lymphocyte activity presentation, thus causing both facets of the immune system to target osteosarcoma tumors. Another study used chitosan-modified molybdenum disulfide (MoS₂) nanosheets loaded with dexamethasone (Dex) as a NIR-responsive nanocarrier (MCD).¹⁴² The positive anti-inflammatory profile of Dex is hampered by quick clearance, which was overcome by loading Dex onto MoS₂ nanosheets. Upon 808 nm laser irradiation, photothermal heat generation occurred leading to controlled drug release making MCD an on-demand remotely operable drug release system. The NIR-irradiated MCD nanoparticles reduced the survival of activated macrophages, which play a role in the progression of OA, while also reducing the excessive secretion of TNF-α, IL-1β, and IL-8. This was also demonstrated in papain-induced OA mice, where MCD injected into the joint cavity led to drug release causing a reduction in inflammatory cytokines, and the increased retention of MCD in the cavities enabled PA imaging. MCD-treated mice had reduced cartilage erosion and improved mobility without any signs of potential toxicity. The remarkable surface area of 2D nanomaterials makes them utilizable for targeted drug delivery in age-related diseases. However, their therapeutic effects might be limited by the type of drug they can carry. Transition metal oxides and dichalcogenide nanomaterials offer a broader therapeutic spectrum. These materials, with their unique combination of catalytic activity, magnetism, and conductivity, can go beyond simple drug delivery. They can be engineered to directly kill diseased cells through heat generation (photothermal therapy) or act as catalysts for targeted drug activation within the diseased cells, providing more potent and versatile therapeutic options for age-related diseases.

3.2.4. Transition metal oxide (TMO) and dichalcogenide (TMD) nanomaterials. Both TMDs and TMOs have been used extensively in research due to their tuneable properties, large surface areas, and high chemical stability at the nanoscale. By fine-tuning their chemical composition, structure, and morphology, their properties can be customised for specific applications. TMDs are composed of transition metal atoms sandwiched between layers of chalcogen atoms (e.g., sulfur, selenium, or tellurium). They exhibit a layered structure similar to graphene, with strong covalent bonds within each layer and weak van der Waals forces between adjacent layers. One of the most well-known members of the TMD family is molybdenum disulfide (MoS₂), and other examples include tungsten disulfide (WS₂), molybdenum diselenide (MoSe₂), and tungsten diselenide (WSe₂).¹⁴³ TMDs exhibit properties such as tunable band gaps, high carrier mobility, and mechanical flexibility, making them promising candidates for several applications. Similarly, TMOs are composed of transition metal atoms bonded to oxygen atoms. Common examples of TMOs include titanium dioxide (TiO₂), zinc oxide (ZnO), iron oxide (Fe₂O₃), and copper oxide (CuO). TMOs exhibit properties like semiconducting, magnetic, catalytic, and piezoelectric properties, which make them suitable for diverse applications. Also, due to their compatibility with scalable synthesis methods such as chemical vapor deposition, hydrothermal synthesis, and sol–gel processes, they make attractive candidates for industrial-scale production.¹⁴⁴ Due to properties like biocompatibility, large surface area and high drug loading capacities, these nanomaterials have been explored against age-related diseases.¹⁴⁵ Immunosenescence, the gradual deterioration of the immune system with age, poses a critical challenge in combating age-related disorders. Addressing this decline in immune function along with increased inflammation is paramount for developing effective interventions as these changes become characteristic pathologies for various age-related disorders. Since infections account for the 3rd biggest cause of death in populations above 65 years,¹¹⁷ it is imperative to look for strategies to defend the elderly against these infections. An excellent example of this was reported where core–shell magnetic iron oxide NPs were synthesised with a catechol group that demonstrated up to 100% killing within 5 minutes of irradiation with NIR light (808 nm) for both Gram-positive and Gram-negative bacteria (including S. aureus).¹⁴⁶ Another prominent photo-mediated nanoparticle therapeutic approach towards reducing inflammation is the in situ generation of CO which is known to act as an anti-inflammatory agent. To this end, a photo-induced flavonol based CO releasing molecule (Fla) was loaded into hollow mesoporous MnO₂ nanoparticles which acted as nanozymes and the nanostructure was further coated with a neutrophil membrane (Fig. 9).¹⁴⁷ The MnO₂ nanoparticles converted ROS into oxygen molecules which in turn caused the oxidation of Fla in the presence of light to generate CO molecules leading to reduction in the levels of ROS as well as pro-inflammatory cytokines showing a synergistic anti-inflammatory effect. The nanoreactors photocatalytically reduce CO₂ to form CO through various repositories that generate CO₂ such as bicarbonate ions, coordinated metal carbonyl compounds,¹⁴⁸ and quinoline frameworks.¹⁴⁹ The strong correlation of cancer with age¹⁵⁰ makes strategies that directly enhance the immune responses an attractive option. Innate immunity-modulating approaches depend on chemokine generation, activation of the cyclic GMP-AMP-stimulator of the interferon gene (cGAS–STING) pathway and enhancement of the recruitment of macrophages. For instance, Fe₃O₄@TiO₂ nanoparticles loaded in neutrophils have been used, which were able to produce ROS, generate chemokines, and enhance the immune cascade.¹⁵¹ Strategies that can activate the active immune system through light responsive FNMs offer a highly precise way to control the activation of different immune pathways.¹⁵²

Fig. 9 Schematic illustration of (A) the preparation of Neu-MnO₂/Fla and (B) neutrophil membrane-targeted in situ CO release for synergistic anti-inflammatory effects promoted by MnO₂ nanozymes. Reproduced with permission.¹⁴⁷ Copyright 2019, Cell Press.

4. Biodistribution, toxicity and clinical status of functional nanomaterials

The effectiveness of drugs significantly depends on their biodistribution. Similarly, biodistribution for nanoparticles decides whether they deliver therapeutic drugs on-site or offsite. Unless they can reach the target tissue site in sufficient concentrations, their efficacy will not be optimal. There are many factors which affect the biodistribution of a nanoparticle such as size, surface charge, type of material, surface functionalization, etc.¹⁵³ Although the mode of administration of nanoparticles is the primary factor which affects the biodistribution, most therapeutic applications would require intravenous injection of nanoparticles to reach the target site. Pulmonary and dermal endothelia allow only very small (<3 nm in size) hydrodynamic diameter (HD) to pass through capillaries.^154,155 Bigger sized nanoparticles can pass through discontinuous and fenestrated endothelia present in capillaries and vessels associated with the kidney and liver. Hence nanoparticles aggregate in these sites. Size is one of the most important factors that alter the retention time of these particles inside the body. Particles of size below 6 nm will be excreted too fast, not allowing for proper therapeutic application. The half-life of particles below 25 nm is less than 4 hours.¹⁵⁶ But the half-life of nanoparticles increases exponentially with the increase in size. Yet, increased size also correlates with a higher clearance due to the reticuloendothelial system. The optimal size lies between 100 nm and 200 nm with optimal retention time and lower ERS clearance.¹⁵⁷ However, some nanomaterials may be smaller to fit their intended purpose such as preventing toxicity due to long-term exposure. Surface charge also changes how particles are cleared and which tissues they selectively aggregate in. For example, if the nanoparticles are negatively charged, it will be difficult for them to pass through the negatively charged glomerular capillaries.¹⁵⁸ Other tissue membranes and barriers such as the BBB also have charge preferences, which makes it important to consider the charge of nanoparticles based on the target tissue site. Along with these factors, the functional groups that are present on the surface of the nanoparticles can change the proteins that adhere to it. Some nanoformulations have pre-conjugated proteins while others do not. However, both the protein conjugated as well as non-protein conjugated nanoformulations will be exposed to proteins in the bloodstream that will adhere to the surface of the nanoparticles based on their functionalization, charge and hydrophobicity. If opsonizing proteins get adhered to the particle, they can trigger inflammation and phagocytosis by leukocytes and hence will start accumulating in lymph organs and hepatic cells for clearance.¹⁵⁹

When we also consider the altered pharmacokinetics of drugs in elderly due to the physiological changes in the ageing body, the situation becomes more complicated. The renal function is usually impaired which enhances excretion, also affecting liver metabolism of drugs including nanodrugs. The serum albumin concentration is also lower which affects the adherence of proteins to the nanoparticle. Chronic inflammation also makes the body more sensitive to therapeutics which can trigger an immune cascade. Overall, all these changes make the absorption of the nanodrug lower in elderly compared to younger individuals.¹⁶⁰ Given the sensitivity of the aging process to small factors and the multifaceted pathologies of many age-related disorders, an evaluation of the toxicity of such nanomaterials is necessary to achieve maximum therapeutic benefit. The toxicity depends on many factors like size, surface functionality and charge, and composition of nanoparticles, all of which should be taken into account while choosing the right nanomaterial class for light-responsive therapeutic applications for age-related disorders. Among lipid-based nanoparticles, liposomes represent a class with the most examples of clinically approved anticancer drug formulations¹⁶¹ Even with chronic dosage studies, liposomes have demonstrated insignificant toxicity in different organs and systemic parameters.¹⁶² However, despite their high biocompatibility profiles, liposomes can still induce immunological activation in some cases depending on their size, charge, and percentage of cholesterol and lipid concentrations.¹⁶³ Ideal formulations are suggested to have a neutral charge and low mol% of cholesterol and lower lipid concentrations.^163,164

The carbon-based materials like carbon dots are highly biocompatible which show low levels of bioaccumulation and rare induction of inflammatory responses. One of the factors affecting the toxicity of carbon dots includes a size above 6 nm (hydrodynamic diameter). Aside from the size, the nature and density of surface charge also play a role in biological interactions with cationic charge, and higher charge density results in oxidative stress, mitochondrial dysfunction, and inflammatory responses.¹⁶⁵ Similar to carbon dots fullerenes also have been reported to induce minimal cytotoxic and immunogenic responses. The fullerene (nC₆₀) nanoparticles show no significant toxicity in C. elegans while its derivatives amino fullerene and UV irradiated nC₆₀ show limited toxicity.¹⁶⁶

Polymeric nanoparticles are among another class of nanoparticles known for their safety profiles. Often used for improving the bioavailability and biocompatibility of encapsulated drugs, many polymeric nanoparticles like poly(lactic acid) (PLA), poly(glycolic acid) (PGA), and poly(lactic-co-glycolide) (PLGA) have been approved by the US FDA and European Medicine agency.^161,167 For plasmonic nanoparticles derived from gold, the toxicity data are two-sided, with many in vitro and in vivo studies reporting little toxicity while others report toxicity based on size, surface charge, and shape, with higher size, higher surface charge, and spherical size being some contributors to toxicity.¹⁶⁸ Unlike relatively non-toxic gold nanoparticles, silver nanoparticles have been shown to exhibit significant levels of toxicity in C. elegans models owing to their metallic nature and dissolution in an aqueous phase.¹⁶⁶ The release of Ag⁺ ions can enhance the toxicity of Ag nanoparticles which can drive toxicity in the skin, eye, respiratory system, hepatobiliary system, kidney, and reproductive system.¹⁶⁹ The potential mechanisms to reduce the toxicity of Ag-nanoparticles include biological methods over physical and chemical ones for synthesis and angstrom-scale threshold for the size of silver nanoparticles to induce minimal toxicity.¹⁶⁹

Upconversion nanoparticles like lanthanide-doped nanoparticles have shown little toxicity in many studies.¹⁷⁰ However, these nanoparticles are still not assessed for long-term evaluation of health risks, secondary toxicity due to decomposition, and detailed effects of accumulation in the body. Reduction in any cytotoxicity can be achieved by the use of various coatings like ethylenediamine tetra(methylene phosphonate) (EDTMP) and poly(maleic anhydride-alt-1-octadecene) (PMAO), as well as thick silica shell coatings that provide higher cell viability than bare UCNPs because of the release of fluoride ions from bare UCNPs.¹⁷¹ Upon toxicity assessment of 2D nanomaterials, it is seen that toxicity is limited in both in vitro mammalian cell lines and in vivo studies for materials. A low and descending order of cytotoxicity has been observed for graphene oxide nanomaterials, layered black phosphorus, and transition metal dichalcogenides (TMDs) like MoS₂ and WS₂. The reduction of toxicity of graphene oxide NPs can be achieved through PEGylation and dispersal in nanocomposite matrices, while for TMDs the type of exfoliation can be a major factor in determining toxicity. These reports of various toxicity assessments highlight that many of the developed nano-formulations available for light-responsive biomedical applications against age-related disorders show limited cytotoxicity and good biocompatibility; however, a low likelihood of cellular damage and immunological activation can be achieved through different physical and morphological modifications to nanoparticles based on their size, surface charge, and surface functionalization.

One of the limitations that specifically needs to be discussed about is the limited penetration of light. Light doesn’t penetrate deep into living tissue for long, but there's debate on what distance to consider as average. The energy from light gets absorbed quickly, with around 95% of light being absorbed within 10–15 mm into tissues (the exact depth varies with different light types). Despite efforts to use different near-infrared light windows, limited penetration remains an unresolved challenge. Several alternative non-invasive therapies have been utilized to overcome this limitation, some of which include electrotherapy or ultrasound therapy. Unlike phototherapy, which relies on light wavelengths for therapeutic effects, electrotherapy involves the use of localized lower voltage currents across the tissues to produce the desired therapeutic effects. Electrotherapy has been shown to reach penetration depths up to 8 mm depending upon the mode of electrotherapy chosen.¹⁷² In one of the modes of electrotherapies, i.e., interference current therapy, a resultant wave is generated which can penetrate deeper into tissues. Ultrasound therapy uses low or high frequency sound waves that penetrate the body tissues and result in the generation of heat within tissues. Ultrasound waves have the potential to penetrate deeper into the body allowing the waves to target body tissues. Ultrasound at a frequency of 1 MHz is absorbed primarily by tissues at a depth of 3–5 cm and is thus recommended for deeper injuries. A frequency of 3 MHz is recommended for more superficial lesions at depths of 1–2 cm.¹⁷³ While looking closely through the alternative strategies for their tissue penetration ability, it is of vital importance to consider the role of light in therapeutics.

Clinical trials have long been a subject of debate when it comes to nanomedicine as the technology can involve materials with established toxicity in higher concentrations. However, this notion is slowly but surely changing as more clinical trials have highlighted the safety and efficacy of various nanoparticle-based treatments across multiple therapeutic areas. For instance, liposomal formulations, such as liposomal doxorubicin, have demonstrated significant efficacy in oncology, particularly in treating ovarian cancer and Kaposi's sarcoma, by improving drug stability and reducing systemic toxicity.¹⁷⁴ The U.S. Food and Drug Administration (FDA) has approved several nanomedicines, marking significant milestones in the journey towards more effective and targeted medical treatments. Doxil, a liposomal formulation of the chemotherapy drug doxorubicin, was approved in 1995. It encapsulates doxorubicin within a liposome, a spherical vesicle with a lipid bilayer. This encapsulation allows the drug to be delivered directly to cancer cells, minimizing exposure to healthy tissues and reducing cardiotoxicity. Another notable example is abraxane, approved in 2005, which is an albumin-bound form of paclitaxel, a chemotherapy drug. Abraxane enhances the solubility and delivery of paclitaxel, allowing for higher doses to be administered with fewer side effects compared to the traditional formulation. This innovation has proven particularly effective in treating breast cancer, non-small cell lung cancer, and pancreatic cancer. Additionally, in the realm of neurodegenerative diseases, nanomedicine strategies have shown promise in enhancing drug delivery across the blood–brain barrier (BBB). Liposomal and polymeric nanoparticles have been utilized to improve the biodistribution and pharmacokinetics of therapeutic agents for Alzheimer's disease, demonstrating positive outcomes in early-phase clinical trials.¹⁷⁵ Furthermore, the successful deployment of mRNA vaccines for COVID-19, using lipid nanoparticles (LNPs) to deliver mRNA, has established a new paradigm in vaccine development, with extensive clinical data supporting their safety and efficacy. These advancements underscore the potential of nanoparticle-based therapies in addressing complex medical challenges, paving the way for future innovations in nanomedicine.

5. Summary and future perspectives

The global increase in lifespan is followed by increments in the incidence of age-related disorders. The process of aging affects all tissues and organs through many common pathways that present as distinct symptoms and pathologies. Coupled with markedly different treatment options, age-related diseases are complicated by the fact that they co-occur with each other and are tricky to treat given the altered pharmacokinetics and pharmacodynamics in the elderly populations. This review highlights a unifying approach to overcome the shortcomings of these conventional therapies using light-activated nanomaterials. In addition to the classical advantages of nanotherapeutics such as increased bioavailability, reduced off-target effects, and longer retention times, the light responsive FNMs enable excellent spatiotemporal control over therapy. Advancements in the field of nanotechnology have enabled the development of nanomaterials that can be activated by light to produce heat, ROS and ultrasound. These capabilities can then be exploited to realize different therapeutic outcomes at the molecular, cellular, and tissue levels. We have focused on different types of organic and inorganic nanosystems activated by light that are commonly effective against distinct age-related diseases. The ability of photothermal treatment to ablate aggregates of proteins has led to excellent clearance of plaques in the case of neurodegenerative diseases like Alzheimer's and Parkinson's, while the same heat generation has enabled clearance of atheroma formation in vasculature leading to atherosclerosis resolution. This has been successful due to the deep penetration capabilities of near-infrared light wavelengths leading to non-invasive treatment options for deep-seated vulnerable tissues like the brain and cardiac vasculature. Following in this direction, it would be interesting for future studies to explore targeting other kinds of age-related aggregation in different organs like fibrosis in the lungs, fatty deposits in the liver, etc. These photoresponsive nanosystems can also help offset the changes occurring in the immune system, which is a key player in many age-related pathologies as well as the entire process of aging. Not only can the heat and ROS generation from these photoresponsive systems help overcome the suppressed state of the immunity in the case of infections and cancers due to immunosenescence, but they can also help limit the effects of immune overactivation in the case of chronic inflammatory conditions like osteoarthritis, by causing the apoptosis of macrophages or helping deliver anti-inflammatory molecules in a controlled manner. Furthermore, these systems can help reduce inflammation to hasten wound healing and tissue repair, another afflicted physiological process in the elderly. Much of the work against aging has been done through nanomaterials either supplementing the immune system or dampening the effect of excessive immune stimulation. It could be greatly beneficial if light-responsive systems that address the reduction in immune function or immune cells can be designed to combat the immunosenescence that occurs with aging. Another important ability of these nanomaterials includes the dissociation or release of drugs in a precise manner. The advantage of this strategy towards age-related disease therapy lies in the prevention of risky side effects in the case of many therapies, as well as the ability to deliver therapeutics in a cyclic or pulsatile manner. This is especially true for hormonal treatments or replacements, which often affect the elderly, and the long and unobserved use of which can lead to serious complications. While these hormonal treatments are being explored in diseases like osteoporosis in great detail, it remains to be seen if the advantage of such controlled therapy can benefit other kinds of hormonal replacement/supplementation therapies such as in the case of estrogen, testosterone, growth hormone, etc. The review finally also talks about senescence which is one of the most targeted hallmarks of aging and one of the most ubiquitous in terms of age-related pathologies. Recent years have seen an upward trend of light-responsive nanomaterials that can not only detect senescent cells using fluorescence but also eliminate them using photodynamic therapy. The heterogeneity of senescence in different tissues, its positive and negative implications for normal physiology, and the absence of distinct localization render senescence an excellent target for the spatial control offered by light-activated systems. Not only can the senescence removal be tissue-specific, but also restricted to ROS-mediated apoptosis in single cells preventing hyperthermia-induced damage to healthy cells. Although light-responsive nanomaterials have also been targeted to senescent cells as a part of age-related disorders, the literature still lacks in this aspect, with most studies focusing on senescence in fibroblasts. In context of using light-responsive nanomaterials against senescence, another unaddressed factor is their ability to prevent the pro-inflammatory and secretory phenotype of senescent cells without killing them. Acheiving the same could potentially prevent several unwanted effects of senolysis such as cancers and defects in wound healing.

The expanding field of nanomedicine holds immense promise for revolutionizing the treatment of various diseases beyond traditional drug delivery, particularly in addressing age-related disorders such as atherosclerosis, neurodegeneration, and osteoarthritis. Despite significant preclinical advancements, there is a critical need for more clinical trials to thoroughly evaluate the safety, efficacy, and therapeutic potential of nanomaterials in these settings. It has been shown that nanomaterials can target and treat more efficiently than conventional treatments. In atherosclerosis, nanomaterials offer novel mechanisms to prevent or reverse plaque formation. In neurodegenerative diseases, they possess the potential to cross the blood–brain barrier and deliver neuroprotective agents directly to affected neurons. For osteoarthritis, nanomaterials can facilitate targeted delivery of anti-inflammatory drugs or support tissue regeneration. Expanding clinical trials in these areas is essential to translate promising laboratory results into tangible clinical outcomes, ultimately improving the quality of life for the ageing population.

With the discoveries of new and promising anti-aging therapies like epigenetic rejuvenation through reprogramming, mitochondrial rehabilitation, and gene therapies to control signalling and prevent DNA damage, also arise the potential risks of uncontrolled treatments that could lead to life-threatening complications like tumors and cancers. Light-controlled nanosystems could provide a pioneering platform for these upcoming therapies, especially in terms of controlling their safety and specificity through real-time monitoring. Although the benefits of such light-controlled nanomaterials are extremely promising and exciting, caution is always warranted because of the rather less investigated toxicity and safety profiles of many nanomaterials for long-term effects, especially in the case of aging where the objective is to minimize damage across tissues. With appropriate research into the safety of these systems, light-responsive functional nanomaterials showcase the ideal capabilities required for tackling age-related diseases which are currently challenged by several deficiencies in therapy and could one day be the mainstay of therapy for the aging populations by significantly enhancing health span and reducing the burden of adverse reactions, drug interactions and polypharmacy.

Author contributions

S. K. S., S. P. and S. J. have contributed equally to this work. J. A. A. H. has provided critical insights into this work. R. V. has conceived the idea and supervised the manuscript. All authors have read and approved the article.

Data availability

This is to indicate that no primary research results, software or code have been included and no new data were generated or analysed as part of this review.

Conflicts of interest

The authors declare no conflicts of interest.

Acknowledgements

R. V. acknowledges the funding support provided by the Department of Biotechnology (DBT), Government of India, for the Ramalingaswami Biomedical Fellowship (BT/RLF/Re-entry/17/2018), the seed grant (I/SEED/RRV/20200076) funded by Indian Institute of Technology, International Research Mobility Grant (I/IMRG/RRV/20210021) and the Core Research Grant (CRG/2023/001189), Science and Engineering Research Board (SERB), Government of India.

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Footnote

† Equally contributed.

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