Applications of nanotheranostics in the second near-infrared window in bioimaging and cancer treatment

Abstract

Achieving accurate and efficient tumor imaging is crucial in the field of tumor treatment, as it facilitates early detection and precise localization of tumor tissues, thereby informing therapeutic strategies and surgical interventions. The optical imaging technology within the second near-infrared (NIR-II) window has garnered significant interest for its remarkable benefits, such as enhanced tissue penetration depth, superior signal-to-background ratio (SBR), minimal tissue autofluorescence, reduced photon attenuation, and lower tissue scattering. This review explained the design and optimization strategies of nano-agents responsive to the NIR-II window, such as single-walled carbon nanotubes, quantum dots, lanthanum-based nanomaterials, and noble metal nanomaterials. These nano-agents enable non-invasive, deep-tissue imaging with high spatial resolution in the NIR-II window, and their superior optical properties significantly improve the accuracy, efficiency, and versatility of imaging-guided tumor treatments. And we discussed the characteristics and advantages of fluorescence imaging (FL)/photoacoustic imaging (PA) in NIR-II window, providing a comprehensive overview of the latest research progress of different nano-agents in FL/PA imaging-guided tumor therapy. Furthermore, we exhaustively reviewed the latest applications of multifunctional nano-phototherapy technologies carried out by NIR-II light including photothermal therapy (PTT), photodynamic therapy (PDT), and combined modalities like photothermal-chemodynamic therapy (PTT-CDT), photothermal-chemotherapy (PTT-CT), and photothermal- immunotherapy (PTT-IO). These imaging-guided integrated tumor therapy approaches within the NIR-II window have gradually matured over the past decade and are expected to become a safe and effective non-invasive tumor treatment. Finally, we outlined the prospects and challenges of development and innovation of the NIR-II integrated diagnosis and therapy nanoplatform. This review aims to provide insightful perspectives for future advancements in NIR-II optical tumor diagnosis and integrated treatment platforms.

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1. Introduction

Advancing “tumor visualization” and “tumor treatment” technology is essential for breakthroughs in tumor theranostics. A variety of effective clinical diagnostic imaging techniques have been developed, such as X-ray computed tomography (X-CT), magnetic resonance imaging (MRI), positron emission tomography (PET), ultrasound, fluorescence (FL), and photoacoustic (PA) imaging.^1,2 These technologies are instrumental in precisely determining the location and size of tumors and offer real-time imaging capabilities. Remarkably, FL and PA imaging technologies stand out due to their ability to identify tumor margins with high sensitivity and spatiotemporal resolution within seconds, all while minimizing the risks associated with ionizing radiation throughout the diagnostic, treatment, and monitoring phases.^3–5 In addition, the biological imaging window has been extended from the visible window (400–700 nm) to the first near-infrared window (NIR-I, 700–900 nm) and the second near-infrared window (NIR-II, 1000–1700 nm).⁶ In the field of biomedical imaging, the NIR II window imaging system surpasses the visible light window and NIR I window due to its distinct advantages.⁷ The longer wavelengths of NIR-II light penetrate deeper into tissues, significantly enhancing the detection of tumors and lesions.⁸ This imaging range also encounters lower autofluorescence interference from tissues, which improves the signal-to-background ratio and results in clearer images. Additionally, NIR-II light undergoes less scattering and attenuation, which optimizes light delivery and enhances image quality. Furthermore, the longer wavelengths of NIR-II induce minimal thermal damage to tissues owing to lower absorption rates.^9,10 The improved resolution and sensitivity of NIR-II imaging allow for more precise delineation of tumor margins and increased detection sensitivity, making it a superior choice for advanced medical diagnostics.

Moreover, NIR-II phototherapy technology is often combined with NIR-II imaging technology to achieve effective tumor treatment or resection under the guidance of accurate tumor imaging, so as to monitor the whole tumor treatment process.¹¹ NIR-II phototherapy has the characteristics of deep tissue penetration, non-invasion, high selectivity, and accurate targeting, leading to potential in minimizing the damage to normal tissues, reducing side effects and promoting the rehabilitation of patients, making it a promising medical treatment method.¹² The applications of NIR-II phototherapy include: photothermal therapy (PTT),¹³ photodynamic therapy (PDT),¹⁴ and combination therapies such as photothermal-chemodynamic therapy (PTT-CDT),¹⁵ photothermal-chemotherapy (PTT-CT),^16,17 and photothermal-immunotherapy (PTT-IO).^18,19 Each of these therapies capitalizes on the unique properties of NIR-II phototherapy to achieve accurate targeted and effective treatment outcomes, indicating the adaptability and potential of NIR-II phototherapy in addressing complex and challenging tumor cases.

By leveraging the distinct advantages of NIR-II optical imaging and NIR-II phototherapy, multi-modal diagnosis and treatment integrated nano-platforms have been constructed. A variety of NIR-II photoresponsive nano-agents with good photostability, bleaching resistance, long fluorescence lifetime, targeting, and high drug loading efficiency can further enrich and enhance the optical diagnosis and treatment capabilities of tumors in the NIR-II window.^20,21 And this integrative treatment effect enables precise targeted treatments, minimizes damage to surrounding healthy tissues, provides real-time monitoring, and adjustment of treatment parameters.

Currently, there is a lack of comprehensive reviews on nano-agents that combine NIR-II FL/PA imaging and phototherapy for tumor diagnosis and treatment. Therefore, in this review, we summarized in detail the latest progress of NIR-II tumor diagnosis and treatment integrated nano-platform (Scheme 1). Firstly, we mainly introduced the design and optimization of nano-agents with optical properties in NIR-II window, and summarized the characteristics of NIR-II FL/PA imaging technology and their application in imaging-guided tumor therapy. Secondly, we analyzed and discussed the advanced NIR-II nano-agents using different photoresponse properties to achieve effective tumor treatment. Finally, the future development prospects and obstacles of NIR-II nano-agents in realm of optical diagnosis and treatment of tumors were discussed. This review is expected to provide illuminating ideas and effective suggestions for subsequent researchers in the NIR-II diagnosis and treatment nano-platform.

Scheme 1 The recent progress in NIR-II biomedical imaging detection and application in cancer treatment.

2. Design and optimization of NIR-II nano-agents

With the continuous development of the research field of NIR-II imaging-guided therapy, various emerging optical nano-agents have been studied, such as single-walled carbon nanotubes, quantum dots, lanthanum-based nanomaterials, noble metal nanomaterials. Under the excitation of NIR-II light with excellent penetration depth and imaging contrast, different materials have exhibited their unique charm and advantages. This greatly broadens the range of materials selection and design for researchers in fundamental studies and clinical transformation application. In this section, we will focus on the properties of various nano-agents as well as their design and optimization to realize bioimaging and cancer treatment in the NIR-II window.

2.1 Single-walled carbon nanotubes

Single-walled carbon nanotubes (SWNTs) are cylindrical nanostructures with diameters ranging from 1 to 2 nm and lengths spanning from 50 nm to 1 cm. SWNTs exhibit a large surface area with all atoms on the surface, capable of chemically or physically connecting many molecules.^22,23 Due to their distinctive physical structures, shapes, surface chemical and optical properties, SWNTs have garnered significant attentions. Actually, the fluorescence emission of SWNTs is the band gap photoluminescence. The band gap between each semiconducting SWNTs is ∼1 eV, which causes electrons to van Hove transitions across the band gap between different energy levels by absorbing certain energy, thus emitting fluorescence.²⁴ By modifying the diameter of carbon nanotubes, incorporating dopants such as nitrogen or boron, or attaching various chemical groups or molecules to influence their electronic structures and energy band gap, it is possible to effectively tune the fluorescence emission wavelength to the NIR-II window, which can reduce excitation scattering and suppress autofluorescence, thus leading to an enhancement of the imaging sensitivity and tissue penetration depth (Fig. 1).²⁵ In view of the excellent properties mentioned above, SWNTs have been extensively studied in bioimaging.

Fig. 1 (a) Absorption spectrum of water alongside extinction spectra for mouse skin and muscle. (b) NIR fluorescence spectra of HiPCO and semiconducting LV SWNTs. (c) Absorption spectra of pristine and separated semiconducting LV SWNTs. (d) The photoluminescence versus excitation map of semiconducting LV SWNTs.²⁵ Reproduced with permission from ref. 25. Copyright 2015 John Wiley and Sons.

Enhancing the water solubility and biocompatibility of SWNTs is crucial for improving their suitability in tissue imaging and guidance during surgical treatments in vivo.^26,27 Modification of SWNTs with amphiphilic polymers, specifically coating them with phospholipid-polyethylene glycol (PL-PEG) after initial treatment with sodium cholate, has proven effective for enhancing solubility and biocompatibility. Welsher et al. used this approach and pointed out that PL-PEG coated SWNTs had low cytotoxicity, which made them suitable for guiding brain tissue imaging compared to other encapsulation methods.²⁸ In addition, protein coating also can diminish the cytotoxicity of SWNTs, such as bovine serum albumin (BSA),^29,30 fibrinogen³¹ and so on.

It was widely recognized that SWNTs own significant excitonic binding and emit light across a wide wavelength range in the NIR-II window. However, the mobility of excitons decreases the photoluminescence quantum yield (PLQY) due to nonradiative processes.³² Interestingly, researchers found that by doping sp³ defects on the surface of SWNTs, these quantum defects produce local potential wells, which could effectively capture moving excitons and enable them to recombine radiatively, resulting in a significant enhancement of the PLQY.^33,34 These defects could be achieved by arylation,^34–37 alkylation^38,39 (Fig. 2). Berger et al. reported a phase-transfer technique using diazonium salts dissolved in organic non-halogenated solvents to selectively react with polymer-wrapped SWNTs, resulting in the formation of aryl defects. After optimization, the PLQY of the SWNTs reached as high as 4% in the NIR-II window.³⁶ All in all, the PLQY of SWNTs was significantly improved by functional group modification.

Fig. 2 Different sp³ modifications on the surface of SWNTs. (a) A range of chemical reactions were chosen to induce luminescent defects in SWNTs.³⁴ Reproduced with permission from ref. 34. Copyright 2021 John Wiley and Sons. (b) The functionalization process for PFO-BPy-wrapped (6, 5) SWNTs using aryldiazonium salts in a toluene/acetonitrile solution with 18-crown-6 serving as a phase-transfer catalyst.³⁶ Reproduced with permission from ref. 36. Copyright 2019 American Chemical Society. (c) Design strategy for the detection of PP_i with sp³-functionalized (6, 5) SWNTs.³⁷ Reproduced with permission from ref. 37. Copyright 2024 Nature.

Besides, in order to apply ultra-low doses of SWNTs to in vivo imaging, the chirality classification of SWNTs has become a breakthrough. Since SWNTs have various chirality,⁴⁰ which correspond to different excitation and emission wavelengths.⁴¹ In mixed chiral SWNTs, non-ideal chiral structures increase energy transfer and non-radiative recombination, thereby reducing the PLQY. Therefore, in pure chiral SWNTs, identical optical and electronic properties minimize these effects, allowing for stronger emission and higher PLQY under limited light excitation.⁴² Chirality purification methods have made progress to date, including aqueous two-phase extraction (ATPE),⁴³ gel filtration,^44–46 DNA wrapping chromatography,⁴⁷ and density gradient centrifugation (DGU).^48,49 Langenbacher et al. obtained single-chirality SWNTs by ATPE, then SWNTs were wrapped with polycarbodiimide polymers.⁵⁰ The results demonstrated that functionalized single-chirality SWNTs could target to specific subcellular compartments, resulting in multiplexed cellular imaging in the NIR-II window.

In a word, through covalent/non-covalent functionalization and chiral purification, the biocompatibility, long circulation in vivo, PLQY, and tumor tissue accumulation of SWNTs have been further optimized. And the application prospect of SWNTs in NIR-II imaging will be broader in future, owing to their extensive surface area and strong fluorescence intensity.

2.2 Quantum dots

Quantum dots (QDs) have gained widespread interest in the fields of bio-optical detection and imaging tracing. The luminescence of QDs is the result of the recombination of an electron and a hole.^51,52 When sufficient energy, at least equal to the band gap (the energy difference between the highest occupied valence band and the lowest unoccupied conduction band), is absorbed by an electron in the valence band, then electron transitions to the conduction band. This movement of the electron leaves behind a hole in the valence band, effectively creating an electron–hole pair by Coulomb force, namely an exciton, which plays a crucial role in the properties of the material.⁵³ When an electron returns to the valence band, it can annihilate an exciton and emit energy as photons (Fig. 3).⁵⁴ In addition, QDs are capable of emitting light in various colors determined by their composition and size. By modifying their structural characteristics, the fluorescence emission can be regulated to the NIR-II window.^55,56 NIR-II QDs exhibit outstanding properties, including excitation across a broad NIR-II wavelength range, emission of narrow and symmetrical spectra, high photostability, stronger photobleaching resistance, and easy decoration of surface properties for targeted biological recognition.^57–60 Crucially, QDs in the NIR-II window have advantages in real-time imaging with higher resolution and non-invasive imaging of deep tissues compared to those in the visible and the NIR-I window.⁶¹ Wang et al. reported a core–shell lead sulfide/cadmium sulfide QDs, which can realize non-invasive cell resolution imaging of mouse head and lymph nodes under the excitation of 1880 nm.⁶²

Fig. 3 (a) Transfer process of semiconductor electronic energy state.⁵¹ Reproduced with permission from ref. 51. Copyright 2009 American Chemical Society. (b) Possible pathways of charge separation and recombination of CsPbBr₃ QDs–benzoquinone and QDs–phenothiazine complexes.⁵² Reproduced with permission from ref. 52. Copyright 2015 American Chemical Society. (c) The alignment of energy bands in a graphene/quantum dot heterostructure.⁵⁴ Reproduced with permission from ref. 54. Copyright 2023 American Chemical Society.

However, QDs as crystals may have lattice defects, which will destroy the periodicity of crystal atoms and produce defect energy levels.⁶³ Therefore, this will lead to an increase in nonradiative relaxation, a decrease in band-edge recombination of electrons and holes, and a decrease in PLQY of QDs. Up to now, a lot of efforts have been made to improve the PLQY of QDs. Zhou et al. synthesized Zn-doped Ag₂Te QDs modified by polyethylene glycol, which PLQY can reach 4.03% (200-fold higher than commercial IR-26 dye) in the NIR-II window.⁶⁴ The principle was that Zn dopant inhibited the crystal defects of QDs, thus reducing non-radiative transitions and then improving the PLQY.⁶⁵ Shu et al. synthesized Pb-doped Ag₂S QDs by “one-pot” synthesis method.⁶⁶ Pb²⁺ made up for the lattice defects that arose from the high mobility of Ag⁺ within Ag₂S nanocrystals. When the ratio of Pb²⁺/Ag⁺ was 2 : 1, the PLQY reached the maximum value of 4.14%. The fluorescence intensity of Pb : Ag₂S was 3.76 times as much as undoped Ag₂S QDs. In addition, some QDs contained heavy metal elements such as cadmium, lead, or tellurium. It was of great significance to develop high biological safety QDs suitable for imaging deep tissues in vivo.^67,68 Zebibula et al. applied a dual-layer coating of silica and amphiphilic polymer (Pluronic F-127) to PbS@CdS QDs, which significantly improved them biological safety and could achieve long circulation in blood vessels for up to 16 h.⁶⁹ There were no obvious signs of infection, allergy and toxic reaction in blood routine and liver and kidney function tests. Awasthi et al. synthesized Ag₂S QDs encapsulated by PEGylated polythiourea dendrimer (PATU) for NIR-II imaging by one-pot method.⁷⁰ The QDs had excellent water dispersibility and biocompatibility. Li et al. reported on BSA-coated Ag₂Te QDs.⁷¹ The BSA coating notably decreased their biotoxicity, enabling their effective to be used in CT/NIR-II imaging of the gastrointestinal tract in mice.

Furthermore, it is worth mentioning that the modified QDs can achieve targeted tumor cell imaging.^72,73 Zhang et al. synthesized Ag₂Te QDs modified by poly(lactic-co-glycolic acid), and QDs were coated with membrane-derived vesicles (CVs).⁷⁴ This NIR-II fluorescence nano-biological probe not only had good biological safety, the ability to effectively escape the phagocytosis of macrophages, and long blood circulation time, but also had obvious homotypic tumor targeting effect (Fig. 4a). Lu et al. enhanced Ag₂S QDs by attaching polyethylene glycol, significantly boosting their blood circulation and tumor targeting capabilities (Fig. 4b).⁷⁵ Tian et al. modified PbS@CdS QDs by attaching an anti-CD3 antibody, increasing their selectivity for cancer-related sentinel lymph nodes (LNs) (Fig. 4c).⁷⁶ Combined with IR-FD (a donor–acceptor–donor dye prepared by fluorene and dioctyl chains substituted 3,4-propylenedioxy thiophene), these QDs served as a dual NIR-II probe for imaging LNs and tumors, assisting in biopsy surgeries, enhancing the understanding of tumor metastasis.

Fig. 4 (a) The preparation and application of Ag₂Te QDs.⁷⁴ Reproduced with permission from ref. 74. Copyright 2019 John Wiley and Sons. (b) The method for preparing PEGylated Ag₂S QDs for in vivo tumor imaging.⁷⁵ Reproduced with permission from ref. 75. Copyright 2020 Elsevier. (c) Sentinel lymph node surgery guided by dual-NIR-II imaging.⁷⁶ Reproduced with permission from ref. 76. Copyright 2020 John Wiley and Sons.

In the future, enhancing the PLQY of QDs while ensuring their biological safety will be crucial. As a traditional and effective fluorescent material, QDs are not only used in basic FL imaging and drug tracing, but also how to detect the target substance more innovatively and intelligently and stably label the whole process of tumor treatment is a direction worthy of researchers’ consideration.

2.3 Lanthanum-based nanomaterials

Lanthanum-based nanoparticles are mainly composed of inorganic matrix and rare-earth-doped ions.⁷⁷ Inorganic matrix generally employed fluorides, oxides, vanadate, oxyfluorides, and other materials with excellent optical transparency, high light damage threshold, and chemical stability. The most commonly used matrices include NaGdF₄,^78,79 LaF₃,⁸⁰ and Na₃ZrF₇.⁸¹ Rare-earth-doped ions mainly include two parts: luminescent center (activator) and sensitizer.⁸² The activators require uniform, discrete energy levels, and long metastable lifetimes, for example, Er³⁺ (ref. 83 and 84) and Tm³⁺ (ref. 85 and 86) are considered excellent activators. Sensitizers are particularly effective at absorbing excitation light and transferring energy to activators, such as Yb³⁺ (ref. 83, 85 and 86) and Nd³⁺.^79,85,87,88 Therefore, by changing the composition of inorganic matrix and adjusting the composition and proportion of rare-earth-doped ions, the fluorescence emission wavelength can be easily adjusted to the NIR-II window, so as to obtain more forceful penetration depth and imaging sensitivity.⁸⁹ There are five basic mechanisms for lanthanum-based nanoparticles to emit FL by up-conversion type: excited-state absorption (ESA), energy transfer upconversion (ETU), cooperative sensitization upconversion (CSU), cross relaxation (CR), and photon avalanche (PA) (Fig. 5a).⁹⁰ The 4f electron orbitals of lanthanide elements are not fully filled and are typically located within the more completely filled 5s and 5p orbitals. When 4f electrons absorb energy, they produce a sharp f-f transition similar to that of atoms. When they jump to a lower energy level again, they release energy and emit fluorescence (Fig. 5b and c).⁹¹

Fig. 5 Mechanism of fluorescence emission of lanthanum-based NPs. (a) Main upconversion processes in lanthanide-doped UCNPs.⁹⁰ Reproduced with permission from ref. 90. Copyright 2014 American Chemical Society. (b) Luminescence spectra of various lanthanide tris(β-diketonates). (c) Simplified diagram showing the definitions of Q^L_Ln and Q^Ln_Ln.⁹¹ Reproduced with permission from ref. 91. Copyright 2010 American Chemical Society.

It is urgent to develop Ln³⁺ doped nanoparticles with efficient emission of in the NIR-II window, to satisfy the demands of sensitive biological imaging.⁹² The brightness of lanthanum-based nanoparticles can be effectively improved by inhibiting the surface-related luminescence quenching effects,⁹³ minimizing the energy migration-induced losses,⁹⁴ and sensitizing by organic dyes.⁹⁵ It has been demonstrated that the inert shell, epitaxially grown on the core nanoparticles, can separate the excited states of the lanthanide ions within the core from the surface quenching centers. This separation helps conserve the NIR-II excitation energy, leading to more efficacious luminescence.⁹⁶ Huang et al. achieved excellent multicolor emission in core–shell lanthanide nanostructures by modifying the atomic vacancies in the inert shell.⁹⁷ Besides, adjusting the process of energy transfer by doping lanthanides is also a good way to enhance the fluorescence emission intensity.⁹⁸ Nd³⁺ was often used to regulate the process of energy transfer, this is because Nd³⁺ is excited to the excited state level after absorbing pump light with different wavelengths, then transits to the metastable ⁴F_3/2 level in the form of non-radiative transition, finally returns to the ground state through the ⁴F_3/2–⁴I_11/2 channel, releasing laser with the wavelength of 1064 nm. Wang et al. synthesized LuPO₄:Nd³⁺ nanoparticles using hydrothermal method, which emitted stable and bright fluorescence at 1064 nm after absorbing laser at 808 nm.⁹⁹ In addition, Yu et al. prepared water-soluble CaF₂:Y³⁺,Nd³⁺ NPs NIR-II luminescent nanoparticles.¹⁰⁰ By doping Nd³⁺, these nano-agents had more excellent fluorescence emission intensity in the NIR-II window.

Traditional fluorescence technology will be influenced and interfered by different absorption and emission spectra in deep tissue structures (including muscle, bone, and fat) during imaging.¹⁰¹ However, lanthanum-based nanoparticles typically exhibit long emission wavelengths and distinct fluorescence lifetimes. And photons generated by lanthanide nanoparticles with different fluorescence lifetimes at the same emission wavelength have different exponential decay rates, which can be used as signals to avoid chromatic aberration that is caused by tissue heterogeneity. This provides a sophisticated method for multi-channel imaging by leveraging the distinct lifetime signals of different fluorophores in the time domain. This technique enables the separation and analysis of multiple signals simultaneously, enhancing the clarity and detail of biological imaging studies.¹⁰² Li et al. developed a lifetime cascade system with temporal domain that span the nanosecond to millisecond (Fig. 6a–c).¹⁰³ The intermediate meso-tetra(4-carboxyphenyl)porphine (TCPP) served as an intermediate energy relay to bridge the energy transfer of long lifetime ZGO:Mn,Eu to the NIR-II lanthanide Yb³⁺ for the generation of a lifetime cascade with a controllable lifetime range across three time domains. Besides, Guo et al. developed a series of NIR-II-emitting β-NaErF₄: 2% Ce@NaYbF₄@NaYF₄ core–shell nanoparticles.¹⁰⁴ By adjusting the thickness of the NaYF₄ inert layer, they could regulate the fluorescence lifetime at 1525 nm from 4.8 ms to 6.5 ms, enabling high signal-to-noise ratio whole-body vascular fluorescence lifetime imaging in mice (Fig. 6d–h).

Fig. 6 (a) The scheme of a lifetime cascade system ranging from nanoseconds to milliseconds in the temporal domain. (b) Proposed mechanism of energy transfer from TCPP to Yb³⁺. (c) Photoluminescence spectra of the energy transfer process of ZGO: Mn, Eu-DNA-1/TCPP-PEI_70K@Yb-Apt_EpCAM.¹⁰³ Reproduced with permission from ref. 103. Copyright 2024 John Wiley and Sons. (d) An energy level diagram depicting the fluorescence emission process of the core–shell–shell nanoparticles. (e) Spectra of fluorescence emission of core–shell nanoparticles. (f) Fluorescence lifetime decay curves recorded at 1525 nm. (g) Fluorescence image of whole-body vascular in mice. (h) Fluorescence lifetime imaging for mapping the entire vascular network in mice.¹⁰⁴ Reproduced with permission from ref. 104. Copyright 2023 John Wiley and Sons.

In summary, NIR-II lanthanum-based nanoparticles, characterized by their extended fluorescence lifetime and high PLQY, represent a promising new approach for the future development of convenient and effective fluorescence labeling tools. By leveraging multiplexing imaging technology, these nanoparticles could significantly enhance the capability to simultaneously image multiple targets, thereby improving the efficiency and accuracy of biomedical imaging applications.¹⁰⁵

2.4 Noble metal nanomaterials

Noble metals typically encompass eight metallic elements, including gold, silver, ruthenium, rhodium, palladium, osmium, iridium, and platinum. By varying the composition of metal elements, reducing agents, templates, and other conditions, it is possible to coordinate the morphology, particle size, and optical properties of various noble metal nanomaterials.¹⁰⁶ According to the size of the particles, the noble metal nanomaterials can be divided into two categories: nanoclusters (NCs) (<2 nm)¹⁰⁷ and nanoparticles (NPs) (>2 nm).¹⁰⁸ Because of their different size, noble metal NCs and NPs show completely different properties. Next, we will summarize the application of noble metal nanomaterials in the NIR-II window biological imaging and therapy based on these two distinctions.

2.4.1 Noble metal nanoclusters. Metal nanoclusters (MNCs) are mainly composed of metal core and ligand motif. The core forms through controlled aggregation of metal atoms and is stabilized by a single-layer motif of metal atoms bonded to organic ligands.¹⁰⁹ This motif, firmly anchored to the cluster core, effectively prevents the MNCs from aggregating into larger nanoparticles or being degraded by etchants into metal–organic ligand complexes, thereby ensuring outstanding solution stability for the MNCs. The protecting ligand layer can consist of thiolate,^110,111 DNA,¹¹² protein,¹¹³ alkynyl,¹¹⁴ and other substances with affinity to the metal core. The size of MNCs aligns closely with the Fermi wavelength of electrons (approximately 0.7 nm), which limits the freedom of electron movement. This confinement causes the continuous energy bands typical of bulk metals to split into discrete energy levels within the nanoparticles. Such quantization is responsible for the pronounced fluorescence emission of MNCs. By carefully selecting different types of ligands and adjusting the quantity of noble metal atoms within the clusters, the fluorescence properties of MNCs can be precisely controlled. This tunability allows the fluorescence emission to span from visible light through to the NIR-I window and NIR-II window, enabling diverse applications in bioimaging and optoelectronics (Fig. 7a).¹¹⁵ For instance, considering AuNCs, within the Fermi wavelength range, the 5d orbital electrons of the AuNCs are closely connected with the nucleus, resulting in a large energy gap between the s orbit and the d orbit, which makes the 5d orbital electrons unable to move in the AuNCs with only a few atoms.¹¹⁶ The electron transition inside the s–p orbit or the electron transition inside the d–sp orbit leads to the fluorescence emission of the AuNCs (Fig. 7b–e). With the advantages of stable optical properties, large displacement, good water solubility, and simple synthesis conditions, NIR-II MNCs are expected to become the new and efficient fluorescent nano-agents to be used in biological imaging and diagnosis.¹¹⁷

Fig. 7 (a) A range of luminescent MNCs showcasing their QY and peak emission wavelengths.¹¹⁵ Reproduced with permission from ref. 115. Copyright 2023 John Wiley and Sons. (b) Normalized excitation and emission spectra (c) Time-resolved PL spectrum (d) matrix-assisted laser desorption/ionization-time of flight mass spectra and (e) schematic representation of the PL origins of PDMAEMA-AuNCs.¹¹⁶ Reproduced with permission from ref. 116. Copyright 2023 John Wiley and Sons.

MNCs synthesized from gold and emitting in the NIR-II spectrum exhibit exceptional fluorescence properties, making them ideally suited for photoactivation and in vivo detection. Bright AuNCs possess deep penetration in biological tissues, and have been successfully used in gastric acid imaging,¹¹⁸ cerebrovascular imaging,¹¹⁹ brain tissue organelle imaging,¹²⁰ marking tumor metastasis, and guiding bone tissue imaging.¹²¹ Additionally, ultra-small AuNCs have the advantage of being safely metabolized and excreted by the body, posing no risk of acute or long-term toxic effects. Although MNCs have been widely developed, compared with QDs and organic dyes, there is still a defect of lower PLQY.¹²² Over recent years, a range of strategies have been progressively devised to enhance the fluorescence efficiency of MNCs, aiming to optimize their optical properties and broaden their applicability in bioimaging, sensing, and optoelectronics, such as alloy NCs (AuAgNCs, AuAgCuNCs),^123,124 surface modification,¹²⁵ and adjustment of metal atom motifs.¹²⁶ Additionally, adjusting ligands is also an effective method to enhance the fluorescence efficiency of MNCs.¹²⁷ The results demonstrated that the luminescence of MNCs could be significantly enhanced by adjusting the structure or interaction between surface ligands molecules.^128–130 Through host–guest interactions, the supramolecular host–guest assembly formed between ligand molecules capped on the metal core effectively inhibits the intramolecular vibration nuclear rotation of the ligand, which greatly prohibits the energy loss process on the surface of nanoclusters, resulting in high PLQY.

Besides being used for FL imaging, MNC was also widely used in tumor treatment because of its excellent long emission wavelength and the ability to produce singlet oxygen (¹O₂) (Fig. 8a).¹³¹ Chen et al. co-modified alkyl thio-substituted NCs with human serum albumin (HSA) and catalase (CAT) to obtain multifunctional nano-agents integrating optics and therapy.¹³² Under the excitation of a 1064 nm laser, these AuNCs produced ¹O₂. Concurrently, CAT catalyzed the decomposition of endogenous H₂O₂ in the tumor microenvironment, releasing O₂ and significantly enhancing the therapeutic efficacy. Dan et al. used AuNCs (BSA@Au) with NIR-II fluorescence and catalase-like activity as photosensitizers.¹³³ AuNCs visualized the tumor location with high signal-to-background ratio (∼7.3) and biodistribution, and realized high-performance imaging-guided photodynamic therapy (PDT) (Fig. 8b). Apart from AuNCs, AgNCs was also extensively used in PDT.^134,135 However, there are few reports about AgNCs used in NIR-II PDT, because the emission wavelength of AgNCs is usually located in the visible window, and AgNCs are prone to oxidation and have poor stability compared with AuNCs, which limits their use in biomedical applications.

Fig. 8 (a) Working principle of the NIR photoactivation of Au44MBA26-NLG.¹³¹ Reproduced with permission from ref. 131. Copyright 2023 American Chemical Society. (b) Scheme of NIR-II BSA@Au enhancing PDT.¹³³ Reproduced with permission from ref. 133. Copyright 2022 Multidisciplinary Digital Publishing Institute.

2.4.2 Noble metal nanoparticles. Noble metal nanoparticles (MNPs) typically range in size from 2 to 200 nm. By selecting appropriate reducing agents, such as sodium borohydride (NaBH₄) or citric acid, the ionic forms of noble metals are reduced to their zero-valent states, enabling the formation of MNPs with varying sizes, morphologies, and dispersibilities. Common morphologies of MNPs include nanospheres, nanorods,¹³⁶ nanostars,¹³⁷ nanosheets/plates, nanodumbbells,¹³⁸ and nanoframes. These distinct morphologies significantly influence the local surface plasmon resonance (LSPR) effect in MNPs. LSPR occurs when MNPs are illuminated, causing the electromagnetic field of the incident light to induce a collective oscillation of the free electrons within the MNPs. Resonance happens when the oscillation frequency of these electrons aligns with that of the incident light, leading to high levels of light scattering and absorption. This property positions MNPs as highly promising for applications such as photoacoustic (PA) imaging and phototherapies like photothermal therapy (PTT) and photodynamic therapy (PDT) within the NIR-II window, even though MNPs don't have the excellent fluorescence performance as MNCs (Fig. 9).¹³⁹ Currently, a variety of plasmonic MNPs have been developed, extending plasma absorption into the NIR-II window and expanding their potential for in vivo cancer diagnosis.

Fig. 9 Schematic illustration of the LSPR excitation in MNPs facilitates photothermal effects, near-field enhancement, and charge transfer, enabling applications in imaging, therapy, and catalysis in biomedicine.¹³⁹ Reproduced with permission from ref. 139. Copyright 2024 John Wiley and Sons.

Because of LSPR effect, MNPs also have the effect of enhancing fluorescence.¹⁴⁰ When the fluorophore is positioned in close proximity the MNPs, the free surface electrons of the noble metal resonate when irradiated by light with appropriate wavelength, which can couple with the fluorophore electrons to change the fluorescence emission intensity. By adjusting the size and morphology of MNPs to change the location and intensity of LSPR and local “hot spots”, or by adjusting the distance between MNPs and fluorophore or interlayer materials, the fluorescence properties of some fluorescent nano-agents/fluorescent organic molecules with poor photostability or low PLQY in the NIR-II window can be improved as shown in Fig. 10a–d.¹⁴¹ Xu et al. reported that the Er³⁺ induced fluorescence emission at 1527 nm of NaGdF₄:Yb,Er, Ce@NaGdF4:Yb,Nd@NaGdF₄ core–shell–shell NPs was enhanced sixfold by coupling with a Au hole-cap nanoarray (Fig. 10e–g).¹⁴²

Fig. 10 (a) Fluorescence intensity of AuNPs with different morphology in the presence of miRNA-21. (b) The distance between miRNA-21-labeled fluorophores and AuNPs corresponding to (a). (c) Fluorescence intensity of AuNPs with different SiO₂ shell thickness in the presence of miRNA-21. (d) The distance between miRNA-21-labeled fluorophores and AuNPs corresponding to (c).¹⁴¹ Reproduced with permission from ref. 141. Copyright 2021 American Chemical Society. (e) The scheme of MEF on Au-HCNA films. (f) Photoluminescence spectra of CSS-DCNPs on glass and on Au50-HCNA. (g) Local E-field enhancement calculated by 3D-FDTD modelling for Au-50 HCNA.¹⁴² Reproduced with permission from ref. 142. Copyright 2023 John Wiley and Sons.

Besides AuNPs, AgNPs also have good electrical conductivity and high density of free electrons, thus them also been extensively utilized in NIR-II PA imaging. Cui et al. fabricated AgBr@PLGA nanocrystals with ultra-high sensitivity and tumor-specific PA properties.¹⁴³ After the GSH activation, AgBr was reduced to AgNPs, and tumor-specific photoacoustography with deep imaging depth could be achieved under NIR-II laser irradiation. Furthermore, the in-band and inter-band electronic transitions of MNPs represent key pathways for non-radiative decay in LSPR. Enhancing these electronic transitions and reducing resistance losses in plasma metals can further refine the electronic structure of the metals, thereby improving its optical properties.¹⁴⁴ Alloying is one of the effective strategies, and different optical properties can be selectively obtained by adjusting the types and the atomic ratio of alloys. Shan et al. reported the NIR-II plasma Au@Au–Ag dot-in-cubic nano-frames, which showed tunable plasmonic properties extending beyond 1400 nm.¹⁴⁵ This was achieved through the selective etching of Ag atoms and the simultaneous deposition of Au and Ag atoms at the edges and corners of the Au@Ag structures. Additionally, when these probes were injected to the depth of about 2 mm under the mouse skin, the PA signal intensity linearly increased with the probe concentration (Fig. 11a and b). Zhang et al. synthesized 2D PtAg nanoplates capable of absorbing broadband light from the NIR-I to NIR-II window (Fig. 11c and d).¹⁴⁶ This alloy nanoplate demonstrated enhanced photothermal and PA effects compared to previously reported Ag nanoplates and Pt nanoparticles.

Fig. 11 (a) The synthesis process of Au@Au–Ag dot-in-cubic nanoframes. (b) Adjustable plasmonic properties across the NIR-I to the NIR-II windows of nanoframes.¹⁴⁵ Reproduced with permission from ref. 145. Copyright 2021 John Wiley and Sons. (c) Ultrathin PtAg nanosheets were used for targeted PTT guided by PA imaging. (d) PA imaging showcased PtAg nanosheet suspensions in the axial and cross-sections of photoacoustic tubes under 1064 nm lasers.¹⁴⁶ Reproduced with permission from ref. 146. Copyright 2021 John Wiley and Sons.

Due to their unique properties, MNPs have given many surprises beyond fluorescence, such as NIR-II PA imaging, metal-enhanced fluorescence, NIR-II PTT effects, and the generation of ROS for NIR-II PDT. At present, among precious MNPs, Au is the most widely accepted and well-known, followed by Ag and Pt. In recent years, Cu has also been recognized as a low-cost material. In the future, it is worthy of attention to develop new MNPs that can replace noble metals, further reduce the experimental and clinical conversion costs, and improve their imaging and therapeutic performance.

3. NIR-II nano-agents for biological imaging

Optical imaging technology has emerged as a crucial research tool in biomedicine due to its non-invasive property and high safety profile. Particularly significant is the biological imaging technology at NIR-II window, which longer emission wavelengths substantially decrease photon scattering in biological tissues while enhancing their light absorption capacity. This permits deeper tissue penetration, enabling imaging with superior temporal and spatial resolution as depicted in Fig. 12a.^147,148 Currently, NIR-II fluorescence imaging and NIR-II photoacoustic imaging are the primary techniques extensively employed for biological imaging diagnosis and treatment of tumors, playing a pivotal role in advancing medical diagnostics and therapeutic strategies.^149–151

Fig. 12 (a) Diagram illustrating the depth of light penetration in tissue at different wavelengths, and interactions like reflection, absorption, and FL.¹⁴⁷ Reproduced with permission from ref. 147. Copyright 2018 Royal Society of Chemistry. (b) Comparative schematic of single-photon and two-photon imaging.¹⁵⁴ Reproduced with permission from ref. 154. Copyright 2022 Frontiers. (c) Illustration of time-resolved lifetime imaging techniques including TCSPC, time-gated, pulse sampling, and frequency-domain techniques.¹⁵⁵ Reproduced with permission from ref. 155. Copyright 2022 John Wiley and Sons.

3.1 NIR-II fluorescence imaging

3.1.1 Characteristics of NIR-II fluorescence imaging. Currently, the primary focus of research in NIR-II window fluorescence (FL) imaging involves the strategic design, selection of core materials and identification elements.¹⁵² A crucial aspect of this process is optimizing the photophysical properties of these nano-agents to ensure they are compatible with existing imaging systems, which is crucial for enhancing the functionality and efficiency of NIR-II probes in capturing detailed, high-quality images for biomedical applications.¹⁵³ Typical characteristics of FL include coupled absorption and emission spectra, PLQY, and the FL signal lifetime. Leveraging these characteristics, enables us to capture relevant signals in the NIR-II window, facilitating a range of imaging techniques, such as NIR-II single-photon FL imaging, NIR-II two-photon FL imaging (Fig. 12b),¹⁵⁴ and NIR-II FL lifetime imaging (Fig. 12c).¹⁵⁵ Each method utilizes the unique properties of the NIR-II window to enhance imaging depth and resolution significantly, making them highly effective for detailed biological observations and diagnostics. By exploring these advanced imaging techniques, we can achieve more precise and comprehensive visualizations in biomedical research and clinical applications.

In the NIR-II window single-photon FL imaging system, the PLQY is a pivotal parameter for evaluating the luminescence efficiency of FL materials. This parameter crucially measures it by comparing the ratio of photons emitted by molecules in their excited state to those absorbed by molecules in their ground state.¹⁵⁶ It is fundamental for optimizing the performance of imaging systems in this spectral range, as it directly influences the efficacy of light conversion from absorbed to emitted photons. By improving the degree of π electron conjugation and molecules rigidity, the PLQY can be improved and the FL emission wavelength can be red shifted to the NIR-II window.^157,158 Moreover, the performance of imaging system is also very important for obtaining effective FL image. Building upon the inherent deep penetration depth of the NIR-II window, a high-sensitivity imaging system can more effectively capture the emission signals of FL substances and provide more accurate anatomical structure, functional, and molecular images. At present, researchers primarily focus on adjusting material structures to obtain higher PLQY to develop noble NIR-II FL nano-agents.

Two-photon FL imaging technology is increasingly recognized as an effective method for significantly enhancing penetration depth.¹⁵⁹ It allows for the absorption of two photons with the same or different frequencies almost simultaneously, and then emits a FL photon through radiation transition. This technique reduces fluorescence background, Rayleigh scattering, and tissue damage while enabling deep tissue imaging to avoid the photobleaching and allowing fluorophores to be excited in a long wavelength window. In addition, it has been made clear that the optimal excitation spectral window of two-photon located in the NIR-II window, which make the research of NIR-II two-photon FL imaging in biological imaging is favored.¹⁶⁰ At present, NIR-II absorption and luminescence materials used in two-photon biological imaging mainly include organic FL groups,¹⁶¹ aggregation-induced emission dyes,¹⁶² carbon dots,¹⁶³ QDs,¹⁶⁴ noble metal nanomaterials and so on.

NIR-II FL lifetime imaging is an imaging technology that uses the intrinsic characteristics of FL materials–FL lifetime, which refers to the time required for the energy loss of excited FL groups to decrease exponentially to 1/e through FL and other non-radiation processes.¹⁶⁵ And the FL lifetime is independent of external factors, such as excitation wavelength, excitation intensity, whether excitation is single photon or multi-photon and photobleaching. The combination of FL lifetime imaging and NIR-II excitation can achieve deep penetration depth and avoid FL scattering of biological tissues, thus achieving high-fidelity multiple detection of multiple analyte biosensors with higher spatial resolution.¹⁶⁶ The technical methods of NIR-II FL lifetime imaging include time gate imaging (TGL)^167,168 and multi-channel optical imaging.¹⁶⁹ At present, the most prevalently used FL materials for NIR-II FL lifetime imaging are nano-agents doped with rare earth elements,¹⁷⁰ and the precise adjustment of FL lifetime can be realized by adjusting the ion concentration and energy conversion process of rare earth elements.

3.1.2 Application of NIR-II fluorescence imaging in biological imaging. NIR-II FL imaging has been extensively researched and applied in the realm of FL-guided drug delivery and precise tumor treatment.¹⁷¹ Under the precise guidance of NIR-II FL imaging, it is possible to achieve comprehensive biological distribution evaluation, real-time monitoring of drug release, and assessment of treatment responses at tumor sites, which can enhance the effectiveness of targeted treatments and providing critical insights into the dynamics of tumor response.¹⁷² Dai et al. synthesized a self-delivering nano-adjuvant (NAs).¹⁷³ Under acidic conditions, NAs responsively disintegrated and released the toll-like receptor agonist resiquimod (R848) utilizing manganese ions (Mn²⁺) as coordination nodes. NIR-II fluorescence imaging was used to guide and monitor the drug release process. Li et al. reported that the micellar nanocarriers were self-assembled from thiophenthiadiazole (TTD)-based NIR-II fluorophores HLAnP, and encapsulated DOX.¹⁷⁴ This material leveraged NIR-II FL imaging technology to achieve precise tumor targeting and real-time continuous drugs delivery, enhancing the efficacy of therapeutic interventions.

Currently, researchers are increasingly focusing on the development of intelligent “off–on” NIR-II FL nano-agents that can be activated by the tumor microenvironment (TME). For example, GSH^175,176 and pH-responsive^177–181 diagnostic FL nano-agents have been designed for tumor imaging to effectively overcome the interference of background signals in normal tissues and enhance the signal-to-noise ratio. Additionally, the activation of FL signal can be realized by coupling the substrate of enzyme in tumor tissue and the specific recognition polypeptide of antibody over-expressed in tumor tissue on the surface of FL nano-agents.¹⁸² Dai et al. prepared a GSH-activated NIR-II diagnostic nanoplatform mediating by iron ion-mediated self-assembly of Ag₂S QD and NIR-II semiconductor polymers (Fig. 13a).¹⁸³ The over-expressed GSH in tumor tissue led to its decomposition via the destruction of metal coordination, thereby turning off the Fluorescence Resonance Energy Transfer (FRET) effect between Ag₂S QD and NIR-II DBZ polymer-based nanoparticles (Pdots) and restoring the FL of Ag₂S QD under the excitation of 808 nm (Fig. 13b and c). Liu et al. proposed Ag₂S vesicles (Ag₂S Ve) assembled by self-assembly of Ag₂S QDs, and then coated with pH-sensitive copolymer thiolated polystyrene-co-poly(4-vinyl pyridine) (Fig. 13d).¹⁸⁴ Under low pH conditions characteristic of tumor tissue, these vesicles triggered the release of Ag₂S QDs and enabled the recovery of NIR-II FL (Fig. 13e). This controllable disassembly method demonstrated specific illumination towards diseased tissue, which provided a powerful strategy for accurate cancer treatment.

Fig. 13 (a) The synthesis of TME activated AFD NPs for tumor specific phototheranostic applications. (b) NIR-II FL recovery of AFD NPs triggered by varying concentrations of GSH. (c) NIR-II FL recovery under different incubation time.¹⁸³ Reproduced with permission from ref. 183. Copyright 2023 John Wiley and Sons. (d) The synthesis of Ag₂S Ve and it's pH-activated FL-guided NIR-II PTT applications. (e) The images of MCF-7 multicellular spheroids incubated with different types of FITC-labeled Ag₂S Ve for 6 h and exposed to 1064 nm laser irradiations (1 W cm⁻²) for 5 min.¹⁸⁴ Reproduced with permission from ref. 184. Copyright 2021 John Wiley and Sons.

Additionally, tumor surgery guided by NIR-II FL imaging represents a cutting-edge technology that precisely delineates tumor edges through targeted imaging of the tumor. And it is anticipated to boost survival rates by facilitating the comprehensive removal of tumor tissues.^180,181 Dang et al. reported a biodegradable, hollow, virus-like neodymium oxide (Nd₂O₃) Nd-nanoprobe, which were modified with cyclic arginine-glycine-aspartic acid (cRGD) pentapeptide (Fig. 14a).¹⁸⁵

Fig. 14 (a) The synthetic method of Nd₂O₃ &NPs-cRGD for NIR-II image-guided breast cancer surgery. (b) The different stages of NIR-II FL-guided tumor surgery in the subcutaneous mouse model. (c) The images of mice from pre-operation (up) and 14 days post-operation (down) after tumor movement under NIR-II FL and white light guidance.¹⁸⁵ Reproduced with permission from ref. 185. Copyright 2024 John Wiley and Sons. (d) The fabrication of DCNPs@Si-omSi-RGD for liver tumor precise resection. (e) The quantitative analysis of fluorescent intensity related to liver tumor surgery. (f) The images of mice from pre-operation (up) and 20 days post-operation (down) after tumor movement under NIR-II FL and white light guidance.¹⁸⁶ Reproduced with permission from ref. 186. Copyright 2022 Elsevier.

Fourteen days post-operation, the group treated with NIR-II imaging-guided surgery using Nd₂O₃&NPs-cRGD showed no signs of local recurrence or metastasis. In contrast, all mice in the control group undergoing surgery guided only by white light, experienced in situ tumor recurrence (Fig. 14b and c). Li et al. designed mesoporous silica shell doped with GSH-sensitive tetrasulfide bond, encapsulated Nd-doped down-conversion nanocrystals, and modified RGD peptide on the surface to target liver tumor tissue (Fig. 14d).¹⁸⁶ At high GSH concentration in tumor tissue, the tetrasulfide bond could be destroyed, which led to the recovery of NIR-II FL explosion. Guided by the NIR-II FL, the solid liver tumor in mice was successfully excised, and without any recurrence within 20 days post-surgery (Fig. 14e and f).

The NIR-II window for FL imaging is increasingly recognized as an exceptional candidate for biological applications due to its deeper tissue penetration and clearer imaging capabilities. Furthermore, the innovation of intelligent “off–on” FL probes elevates NIR-II imaging technology to unprecedented levels. Rendering it is pivotal not only in fundamental research but also in clinical settings where it provides highly accurate image-guided treatments. Consequently, the utilization of NIR-II FL nano-agents holds immense potential for advancing tumor diagnosis and therapy, offering invaluable assistance in both research laboratories and clinical environments.

3.2 NIR-II photoacoustic imaging

3.2.1 Characteristics of NIR-II photoacoustic imaging. In contrast to traditional FL imaging, photoacoustic (PA) imaging represents a distinct imaging modality that relies on detecting acoustic waves rather than light signals.¹⁸⁷ The core principle of PA imaging involves the absorption of photons by biological tissues under laser irradiation, leading to thermoelastic expansion. This expansion generates acoustic waves, which are then captured by an acoustic wave detector to create images. One notable advantage of using acoustic waves, or phonons, is their reduced scattering in biological tissues compared to photons. As a result, PA imaging offers superior tissue contrast, enhanced spatial resolution, and the capability for deeper penetration into tissues. These characteristics make PA imaging particularly favorable for comprehensive structural and functional imaging, providing a clearer and more precise visualization of tumor biological structures.^188,189

The scattering effect of biological tissues is pronounced at shorter wavelengths (200–700 nm), leading to an exponential decrease in light intensity and PA amplitude with depth increasing.¹⁹⁰ In contrast, the NIR-I and NIR-II window exhibits lower blood absorption and improved light penetration, making it extensively used for deep tissue imaging.¹⁹¹ Recent advancements have focused on PA imaging technology in the NIR-II window, which has garnered attention due to its low sound scattering properties.¹⁹² This characteristic allows it to overcome the diffusion limit of light, achieving a penetration depth of up to 5 cm,¹⁹³ thereby facilitating multi-scale, high-resolution imaging of biological structures ranging from organelles to entire organs.^194,195 Additionally, imaging contrast is significantly enhanced in the NIR-II window due to the absence of background interference from non-absorbing tissue components. Most importantly, the Maximum Permissible Exposure (MPE) for humans is higher in the NIR-II range, permitting the utilization of higher intensity pulsed lasers and resulting in a stronger PA signal.^196–198 Therefore, NIR-II PA imaging offers substantial improvements over NIR-I PA imaging, in both basic research and practical applications. Overall, NIR-II PA imaging, with its 3D stereoscopic depiction and deeper penetration capabilities, merges the benefits of optical and acoustic imaging. This integration resolves the limitations of NIR-I PA imaging and FL imaging in tumor diagnostics, presenting a more effective and detailed approach.

In addition to choosing the appropriate wavelength for PA imaging, it is crucial to develop a variety of NIR-II PA contrast agent with high NIR-II absorption rates and efficient PA signal conversion capabilities in order to improve the PA imaging performance.^199,200 Recent advancements have seen a surge in the creation of exogenous NIR-II PA contrast agents, which boast high molar extinction coefficients (MEC), low PLQY, and excellent photostability, making them highly effective for PA imaging purposes. Various categories of materials are being explored for this purpose, including metal nanomaterials,^201,202 organic semiconductor conjugated polymers,^203–206 QDs,²⁰⁷ small molecular organic dyes^208,209 and so on. He et al. adjusted the LSPR peak of GNR into the NIR-II window by coating SiO₂ on gold nanorods, which enhanced the PA imaging capabilities and improved its photothermal stability.²¹⁰ Zheng et al. made inorganic nanoparticles have strong NIR-II absorption by adjusting the silicon–carbon ratio in zeolite–carbon-based nanozymes, resulting in excellent PA imaging performance.²¹¹ Jiang et al. used the donor–receptor–donor structure and active intramolecular motion to design an organic small molecular structure, the NIR absorption peak is red-shifted to obtain excellent NIR-II PA imaging performance.²¹² These innovative designs have significantly advanced research on NIR-II PA nano-agents, which is anticipated to unlock new possibilities in non-invasive imaging technologies and clinical applications.

3.2.2 Application of NIR-II photoacoustic imaging in biological imaging. NIR-II PA imaging, known for its consistent contrast, holds significant potential in the field of biomedicine. It offers superior spatial resolution and deeper imaging depth, enabling comprehensive insights from the level of organelles to entire organs. Therefore, NIR-II PA imaging is expected to provide guidance for cancer screening, diagnosis and treatment. At present, this imaging technique has been extensively applied in the context of tumor therapy^213–216 and in situ brain tumor imaging.^217,218

Furthermore, NIR-II PA imaging significantly enhances capabilities in the realm of deep tumor imaging. In vitro experiments demonstrated an impressive imaging depth of up to 5 cm in chicken breast tissue, while in vivo studies on mice show a imaging depth of approximately 2 cm. Wu et al. synthesized a semiconducting polymer based on thienoisoindigo that exhibited strong absorbance in NIR-II window.²¹⁹ This polymer could be effectively imaged through chicken breast tissue samples as thick as 5.3 cm using 1064 nm laser excitation. Chitgupi et al. reported a micelle formed from NIR-II absorbing cyanoalkyl phosphate (CYFAP) salt dye, which could be imaged by chicken breast tissue of 11.6 cm in vitro.²²⁰ The NIR-II PA imaging technique was successfully applied to imaging human breast cancer by utilizing it on three female volunteers through compressed breast tissue, achieving imaging depths ranging from 2.6 to 5.1 cm (Fig. 15a–e). Additionally, developing contrast agents with high permeability represents a promising strategy to enhance the contrast of NIR-II PA imaging in deep tumor tissues. Li et al. proposed that hyaluronidase and Ag₂S nanodots were encapsulated by acid-labile metal–organic framework, which could be passively transported to the tumor and catalyze the breakdown of hyaluronic acid around the tumor tissue. Thus, achieving deep penetration, and Ag₂S nanodots exhibited significant NIR-II PA signal under the excitation of 1064 nm (Fig. 15f–g).²²¹ Li et al. proposed a Janus AuNR-Pt nano-motor (JAuNR@Pt) driven by H₂O₂. In mice treated with it, the NIR-II PA signal intensity at depths of 1.8 mm and 3.6 mm was increased by approximately 20% and 76%, respectively, compared to those treated with AuNR@Pt (Fig. 15h–k).²²² Moreover, because the acoustic waves in PA imaging are the signal obtained after the biological tissues absorb photons and produce thermoelastic expansion, the temperature usually rise in the process of PA imaging. Therefore, innovative designs incorporating temperature sensitivity have significantly broadened the applications of NIR-II PA imaging. Li et al. described a reversible temperature-responsive tungsten-doped vanadium dioxide nanoparticle (W-VO₂@PEG) coated with polyethylene glycol (Fig. 16a).²²³ This NPs transitioned from a metal phase to an insulator phase when the temperature rose from 35 °C to 45 °C. During this phase changed, W-VO₂@PEG NPs exhibited a significant increase in NIR-II light absorption, the PA signal amplitude at 1064 nm escalated by as much as 260% (Fig. 16b and c). Sun et al. also used a similar W-VO₂@PEG NPs material to achieve the quantitative 3D temperature rendering of deep tumors (Fig. 16d).²²⁴ When the temperature increased from 35 °C to 45 °C, the PA signal amplitude at 1064 nm increased by 2 times (Fig. 16e).

Fig. 15 (a) Surfactant-stripped CyFaP (ss-CyFaP). (b) The imaging setup. (c) A container filled with chicken breast was used for in vitro penetration depth test. (d) Overlaid with US images in grayscale, showing differences between tubes filled with water and ss-CyFaP micelles. (e) SNR of PA signal as a function of tissue thickness on top of the tube.²²⁰ Reproduced with permission from ref. 220. Copyright 2019 John Wiley and Sons. (f) The Preparation and Tumor Penetration of AHZ NPs. (g) The images of Ag₂S or AHZ in 4T1 tumor cell spheroids penetrated.²²¹ Reproduced with permission from ref. 221. Copyright 2022 American Chemical Society. (h) The preparation of JAuNR-Pt nanomotor and its application. (i) Comparison of PA signal intensities at various time points post-injection of JAuNR-Pt nanomotors versus AuNR@Pt. (j) Corresponding PA signal intensity of tumor in vivo at 24 h. (k) Corresponding PA signal intensity in the different depths at 24 h.²²² Reproduced with permission from ref. 222. Copyright 2022 American Chemical Society.

Fig. 16 (a) The dynamic-enhanced NIR PA imaging using W-VO₂@PEG NPs triggered by near-human-body temperature. (b) PA imaging of W-VO₂@PEG NPs and graphene samples at different temperatures.²²³ Reproduced with permission from ref. 223. Copyright 2022 American Chemical Society. (c) The synthesize of W-VO₂@PEG NThems and its application of quantitative 3D temperature rendering of deep tumors. (d) The depth PA imaging of the W-VO₂@PEG NThems in an agar phantom sample. (e) X–Z tomographic imaging at different temperatures of (d).²²⁴ Reproduced with permission from ref. 224. Copyright 2023 American Chemical Society.

In the future, the NIR-II window severs as an ideal response window of PA imaging, will significantly improving the precision of tumor tissue localization and facilitating tumor treatment guidance by PA imaging.

4. NIR-II imaging guided NIR-II phototherapy

In recent years, phototherapy has emerged as a highly effective method for treating tumors. The NIR-II window broadens the depth of tumor treatment and provides a powerful means for tumor detection and treatment. Nano-agents with NIR-II FL imaging or PA imaging performance can effectively kill tumor cells through PTT, PDT, PTT-CDT, PTT-CT, and PTT-IO. These technologies not only allow for precise visualization of tumors but also facilitate targeted treatment strategies, thereby realizing a dual breakthrough in cancer management.

4.1 NIR-II imaging guided NIR-II PTT

The therapeutic and diagnostic nano-agents combining NIR-II optical biological imaging with high sensitivity and high penetration depth with PTT have been considered as an advanced technology to improve detection and treatment. The semiconductor polymer TRPV1 prepared by Wu et al. can even be used to realize brain imaging and treatment without implantation.²²⁵ PTT represents a prominent photon-triggered therapeutic modality that eradicates tumor cells through localized heating, which is generated by photothermal agents activated by visible or NIR light.^226,227 Notably, compared with visible light and NIR-I window PTT, NIR-II window PTT has more advantages. This is because there is lower light absorption and scattered light in the NIR-II window, which allows deeper tissue penetration. Additionally, the maximum permissible exposure (MPE) intensity in the NIR-II window is higher-1 W cm⁻² for 1064 nm, 0.72 W cm⁻² for 980 nm and 0.33 W cm⁻² for 808 nm-enhancing both the safety and efficacy of the treatment. These attributes make NIR-II PTT a more effective option for targeting deeper-seated tumors with minimal damage to surrounding tissues.^228,229

At present, PTT guided by NIR-II PA imaging offers considerable advantages, because the heat energy generated during PA imaging can be utilized directly to treat tumors. This method eliminates the need for adding extra photothermal agents or fluorescent dyes, streamlining the treatment process and potentially reducing side effects associated with additional compounds.^230–234 Li et al. described the synthesis of a semiconductor polymer nanoparticles (SPNs) prepared by the NIR-absorbing SPNs (PFTDPP) and SnO-based NO Donors (S-nitro so-n-acetyl cellulose, Snap), which could generate heat through vibration relaxation and provide NIR-II FL/PA imaging to guide PTT.²³⁵ Shao et al. reported the titanium nitride QDs (Ti₂NQDs) prepared from nitride-based MXene, which showed excellent photothermal performance and strong photothermal stability under laser irradiation in both NIR-I (808 nm) and NIR-II (1064 nm) biological windows, and the experimental group showed complete tumor ablation under the guidance of PA imaging.²³⁶

Photothermal conversion efficiency (PCE, η) is a critical parameter of photothermal agents, directly influencing the required intensity of irradiation light.^237,238 The use of high-intensity light to activate photothermal agents can inadvertently harm healthy skin and tissues. Consequently, it is very important to develop photothermal agents with high PCE to reduce the radiation intensity and improve the safety of PTT for living tissues. Some nano-agents with excellent PCE are shown in Table 1. For inorganic NIR-II photothermal agents, enhancing NIR-II absorption is commonly employed to augment the photothermal effect.²³⁹ AuNPs are extensively utilized in the field of PTT due to their ability to generate efficient local heating through the excitation of LSPR (as discussed in 2.4.2 above).^240–244 Ding et al. constructed Au@Dopamine, and its PCE was 75.7% (1064 nm, 1.0 W cm⁻²).²⁴⁵ Even with an 8 mm thickness of in vitro pork tissue, the temperature of the NPs solution increased to above 40 °C. Chen et al. prepared AuNPs coated UiO-66-NH₂ (NMOF).²⁴⁶ By adjusting the growth of Au nanoshells, with the peak value exceeding 1300 nm and the PCE as high as 74.0%. In addition, ultra-thin two-dimensional (2D) nanomaterials have interesting physical and optical properties, which provide new possibilities for realizing efficient photothermal agents with high extinction coefficient and high PCE.^247–249 Organic semiconductor polymer nano-agents have the characteristics of optically adjustable NIR-II window. By designing donor–acceptor (D–A) structure, they can show strong absorption extinction and high PCE. Adding weak electron donor units to the semiconductor skeleton to inhibit the non-radiation decay pathway can effectively improve NIR-II absorption.^250–252

Table 1 Classification of different photothermal nano-agents and their PCE at different excitation wavelengths

Classification of nano-materials	NIR-II photothermal agent	λ ex/λem [nm]	PCE %	Ref.
AuNPs	TA–Si–Au	1064	24.1	240
	Au/Ag core/shell NRs	1064	28.8	241
	AuNCs@SiO2 nanochains	1064	82.2	242
	Janus Au-PbS NPs	808/1300	45.16	243
		808/1500	63.27
	AuPd-GOx-HA (APGH) nanocatalysts	1064	50.7	244
	Au@PDA/PEG-PI (T-NPs)	808	86.6	245
		1064	75.7
	Gold nanoshells on UiO-66-NH2 (UGs)	1064/1300	74.0	246
2D nanomaterials	TeO2/(NH4)xWO3 nanoribbons (TONWNRs)	1064	43.6	247
	2D SnTe@MnO2-SP NSs	808	38.2	248
		1064	43.9
	PNS/PEG-Ag2S QDs	808/1050	52.46	249
Organic semiconductor polymer nano-agents	AuGSNO	1064	80.0	250
	SP4 NPs	1064	46.5	251
	Semiconducting polymer P2 based NPs (P2NPs)	1064	38.8	252

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Additionally, the single bond linkage between the donor and acceptor in multiple-acceptor D–A type polymers potentially bestows them with a wealth of flexible intramolecular rotors along the polymer backbone. These rotors are considered highly advantageous for promoting active intramolecular motion, which in turn induce an effective photothermal effect. Theoretically, this arrangement can significantly enhance the PCE in aggregates, potentially leading to the improvement of performance in photothermal applications.²⁵³

4.2 NIR-II imaging guided NIR-II PDT

NIR-II PDT involves the activation of photosensitizers by NIR-II laser irradiation, the photosensitizers absorb energy and transfer it to molecular oxygen, generating reactive oxygen species (ROS), such as hydroxyl radical (˙OH), singlet oxygen (¹O₂), and superoxide (O₂˙⁻), which leads to oxidative stress and triggers apoptosis in tumor cells.^254,255 Two primary forms of ROS production exist: photosensitizer molecules are excited from the ground state to the singlet excited state upon photoexcitation. They are then excited to the long-lived triplet excited state via cross-process between systems, which can undergo electron transfer reaction with biological substrates/chromophores to generate free radical anions, and the free radical anions further interact with oxygen to generate ˙OH and O₂˙⁻ (the type I reaction).^256–260 Alternatively, the excited state energy of triplet photosensitizer molecules can be transferred to oxygen to generate ¹O₂ (the type II reaction).^261,262

Currently, the field of NIR-II imaging-guided NIR-II PDT is experiencing a surge in groundbreaking research, exploring innovative techniques that enhance the efficacy and precision of this therapeutic approach. It has been demonstrated that certain NIR-II FL dyes, such as cyanine dyes,^263,264 porphyrins and their derivatives^265,266 can produce ROS under NIR-II laser irradiation. Furthermore, photosensitizers with low PLQY, such as phthalocyanine and naphthalene phthalocyanine^267,268 are effective as PA contrast agents due to their robust absorption in the NIR-II window. Consequently, these small molecular photosensitizers enhance the therapeutic efficacy of NIR-II PDT by serving as dual roles: as therapeutic agents and as NIR-II contrast agents, thereby optimizing treatment outcomes.^269,270 In addition, the biocompatibility and photostability of photosensitizers can be further improved by loading/encapsulating them in inorganic NPs or forming semiconductor polymers though self-assembly, which also improves the targeted delivery to tumor cells and boosts the production of ROS, effectively enhancing the capability to eradicate tumor cells.^271–275

Even more interesting is that among many inorganic nano-agents, up-conversion NPs can be used not only as carriers and NIR-II FL emitting materials, but also as energy converters to activate the attached photosensitizers via FRET, enabling deep-tissue PDT.^276–278 Er³⁺-doped UCNPs can be used to excite IR808²⁷⁹/Ce6²⁸⁰ photosensitizer via energy transfer to enhance the NIR-I-excited PDT, and be used to excite ZnPc photosensitizer to enhance the NIR-II-excited PDT.²⁸¹ In addition, some nano-agents can directly generate ROS for tumor treatment in the absence of organic photosensitizers,²⁸² which has following advantages: (1) higher photostability; (2) resistance to enzymatic degradation; (3) superior molar extinction coefficient, at least 3–7 orders of magnitude higher than that of most organic photosensitizers; (4) tunable light absorbs to a longer wavelength, resulting in deeper tissue penetration. Plasma MNPs have the characteristic of LSPR, which can generate two types of high-energy charge carriers under laser irradiation, namely electrons and holes. The generated high-energy charges can promote the generation of ROS through the energy conversion process, which endows plasma MNPs with photodynamic characteristics.^283,284 Meng et al. synthesized plasmonic Bi₂S_3−x–Au@HA heterostructure nanocomposites (Fig. 17a).²⁸⁵ The modified AuNPs can accept e⁻ on the Bi₂S_3−x semiconductor conduction band and transfer it to O₂ for generating O₂˙⁻, which can be further oxidized by h⁺ to ¹O₂ under 1064 nm laser irradiation (Fig. 17b and c). In addition, bimetallic QDs, carbon dots QDs and graphene QDs can induce ¹O₂ to generate ROS by transferring energy from excited QDs state to ground state triplet oxygen, which is called triplet energy transfer (TET). Chen et al. reported an effective photosensitizer Cu_2−xSe QDs, which could efficiently generate dreadful ROS (˙OH and ¹O₂) by NIR-II (1064 nm) laser to trigger PDT (Fig. 17d).²⁸⁶ Wang et al. reported UCNPs@SiO₂-GQD, upon 980 nm laser irradiation, allowed NaYF₄:Yb³⁺,Er³⁺ UCNPs to emit green and NIR FL.²⁸⁷ The green FL aligned with the excitation band of GQDs, facilitating energy transfer from UCNPs to GQDs. This interaction resulted in the generation of ¹O₂ and produced additional NIR FL (Fig. 17e).

Fig. 17 (a) The main synthesis procedure, ROS generation and antitumor mechanism of Bi₂S_3−x–Au@HA. (b) The proposed charge separation/transfer in Bi₂S_3−x–Au@HA and ROS generation mechanism. (c) The images of 4T1 cells stained with DCFH-DA to detect ROS generation following different treatments.²⁸⁵ Reproduced with permission from ref. 285. Copyright 2023 Elsevier. (d) The Construction of CS/Cu_2−x Se-TPZ Nanoplatform.²⁸⁶ Reproduced with permission from ref. 286. Copyright 2023 American Chemical Society. (e) Scheme illustrating the design of GUCNPs.²⁸⁷ Reproduced with permission from ref. 287. Copyright 2021 Royal Society of Chemistry.

4.3 NIR-II imaging guided NIR-II combinational phototherapy

Although NIR-II-guided single PTT and/or PDT exhibits considerable promise in the treatment of cancer, there is a bottleneck in its single method that prevents the therapeutic effect from being further enhanced. Adopting combinational therapies, which combine NIR-II PTT with CDT, CT and IO, are the promising strategy to overcome this bottleneck. Under the guidance of NIR-II imaging, these multi-elements combined therapies offer a promising approach to achieve a synergistic “1 + 1 > 2” anticancer effect, which can further overcome the defects of insufficient photothermal killing ability, multidrug resistance, and poor metastasis prevention ability.

4.3.1 PTT and CDT. CDT capitalizing on the intrinsic biochemical properties of the TME to activate the Fenton and Fenton-like reactions, generating potent oxidative hydroxyl radicals that selectively damage tumor cells while sparing healthy tissue.²⁸⁸ (Formula (1)–(3)) The advantages of CDT include: (1) no restriction on the depth of field penetration; (2) minimal adverse effects on healthy tissues; (3) no equipment requirement; (4) no multidrug resistance; and (5) increased creation of ROS. While CDT has proven effective in inhibiting tumor growth and metastasis, completely eradicating tumors remains challenging due to the insufficient levels of endogenous hydrogen peroxide (H₂O₂).^289,290 Additionally, the therapeutic efficacy of Fenton or Fenton-like reactions is still unsatisfactory due to their weak reaction kinetics, which severely limits the further application of CDT. It is currently acknowledged that using NIR-II PTT to improve CDT is a very promising treatment because PTT can significantly enhance the ionization process in the Fenton-like reaction, thereby increasing the production of ROS and facilitating an effective combination with CDT.²⁹¹ Specifically, kinetic studies have demonstrated that raising the temperature from 20 to 50 °C can accelerate the Fenton reaction by up to four-fold, highlighting the pivotal role of NIR-II PTT in augmenting CDT.²⁹² Moreover, the local increase in temperature also boosts blood flow and enhances oxygen delivery to the tumor site. This, in turn, supports the β-lapachone cyclic reaction, leading to prolific generation of H₂O₂, which helps overcome the inherent deficiency of endogenous H₂O₂ in the TME.²⁹³

Fe²⁺ + H₂O₂ → Fe³⁺ + (OH)⁻ + ˙OH (1)

H₂O₂ + 2Fe³⁺ → 2Fe²⁺ + O₂ + 2H⁺ (2)

O₂ + Fe²⁺ → Fe³⁺ + O²⁻ (3)

At present, a variety of nano-agents with good photothermal properties have been developed, which can effectively promote CDT to kill tumor cells through photothermal stimulation under the NIR-II. Such as Bi nanodots,²⁹⁴ Fe/Mn bimetal-doped ZIF-8,²⁹⁵ Fe-doped polyoxometalate (Fe-POM),^296,297 carbon-encapsulated magnetite nanodoughnuts,²⁹⁸ Pt@V₂C MXene,²⁹⁹ Cu₂O-supportedmolyb-denum disulfide (MoS₂) nanoflowers,³⁰⁰ Cu_2−xTe nanosheets,³⁰¹ ultrathin 2D transition metal chalco-genides (TMCs) nanosheets (NSs),³⁰² nickel-based nanomaterials,³⁰³ CuS NPs,^304,305 Ag₂S–Ag Janus probes.³⁰⁶ In recent years, Cu⁺-mediated CDT has also been widely studied. Li et al. reported a dual-plasmonic Au@Cu_2−xSe core–shell nanocrystals (dpGCS NCs) (Fig. 18a), facilitating tumor-specific CDT through the production of ˙OH triggered by TME-activated dpGCS NCs-catalyzed in situ Fenton-like reactions, which were further enhanced by NIR-II laser exposure.³⁰⁷ Besides, the robust NIR-II LSPR absorption of dpGCS NCs significantly enhanced their photothermal performance for NIR-II PTT, as depicted in Fig. 18b and c. Zhang et al. designed and synthesized an oxidized molybdenum polyoxometalate-Cu nanocomposite (Ox-POM@Cu) (Fig. 18d).³⁰⁸ The inclusion of Cu in Ox-POM@Cu created oxygen vacancies, increasing carrier concentration, accelerating electron transfer, and enhancing redox activity, thus providing efficient catalysis (Fig. 18e and f). In addition, this composite also served as an NIR-II PA imaging probe and a cancer therapy agent. In a similar vein, Li et al. developed an elesclomol (ES) loaded Cu₂O nanocomposite (PEG@Cu₂O-ES) (Fig. 18g).³⁰⁹ The NIR-II induced PTT effect of Cu₂O speed up the release of Cu⁺, generating a high level of ROS that attacked the ATP-Cu pump on cancer cell membranes, thereby aggravating Cu overload and effectively killing tumor cells (Fig. 18h and i).

Fig. 18 (a) The synthesis of RGD-dpGCS NCs and its therapeutic mechanism for NIR-II phototheranostics. (b) The image of U87-MG cancer cells after various treatments. (c) The images of calcein-AM/PI co-stained U87-MG cells after various treatments.³⁰⁷ Reproduced with permission from ref. 307. Copyright 2021 John Wiley and Sons. (d) The preparation, PAI, and therapeutic mechanism of Ox-POM@Cu nanoenzyme. (e) Evaluation of drug efficacy of Ox-POM@Cu. (f) The images of live and dead 4T1 cells with calcein-AM/PI double staining and different treatments.³⁰⁸ Reproduced with permission from ref. 308. Copyright 2021 John Wiley and Sons. (g) The cuprous oxide nanocomposites for inducing Cu proptosis in breast cancer. (h and i) The live & dead images and fluorescence statistics of 4T1 cells after treatment with NIR-II.³⁰⁹ Reproduced with permission from ref. 309. Copyright 2024 Elsevier.

Loading enzymes that can catalyze the CDT reaction onto a carrier with PTT capability to achieve synergistic treatment of both therapeutic approaches is also a promising approach.³¹⁰ Li et al. reported a plasmonic trienzyme-integrated metal–organic framework (plasEnMOFs) nanoplatform, which incorporated NIR-II plasmonic Au nanorods and natural enzymes—catalase (CAT), glucose oxidase (GOx), and horseradish peroxidase (HRP)—within zeolite imidazolate framework 8 (ZIF-8) MOFs.³¹¹ Thus, it effectively reduced intratumor glucose levels and produced toxic ROS for simultaneous starvation therapy and CDT, complemented by plasma thermotherapy. Additionally, the NIR-II PTT effect further boosts glucose depletion and ROS generation. Yang et al. reported that by conjugating GOx with strontium copper tetrasilicate (SrCuSi₄O₁₀) nanosheets (NSs).³¹² The photothermal effect of it could amplify the catalytic activity of GOx under NIR-II exposure, markedly increasing the depletion of intertumoral glucose and the production of H₂O₂, thereby enhancing the effectiveness of the therapy.

Nano-agents possessing enzyme-like properties offer an innovative approach to cancer treatment by generating a substantial quantity of ROS, thus reducing reliance on the sole use of NIR-II PTT. Additionally, NIR-II PTT can significantly enhance the ionization process in the Fenton-like reaction, boosting ROS production. This therapy also increases blood flow and oxygen supply at the tumor site, which strengthens the β-lapachone cyclic reaction, leading to copious H₂O₂ generation. Overall, the synergistic integration of NIR-II PTT with CDT harnesses their complementary strengths, optimizing the therapeutic impact and broadening the scope for effectively targeting and eliminating tumor cells.

4.3.2 PTT and CT. Chemotherapeutic agents exert their therapeutic effects by destroying or interfering with critical biomolecules such as DNA, proteins, and lipids within tumor cells. This disruption leads to cellular dysfunction, ultimately inducing apoptosis or necrosis—processes known collectively as cytotoxic effects.³¹³ However, CT has serious defects, such as the systemic toxicity, and tumors resistant to long-term CT.³¹⁴ During the treatment process, it was found that NIR-II PTT treated tumor cells were more likely to respond to CT drugs, and NIR-II PTT photosensitizers can encapsulate CT drugs and provide targeting function,³¹⁵ reducing the toxic side effects of CT drugs.^316,317 Additionally, the heat energy produced will facilitate the release of medications more effectively, enhancing their potency.³¹⁸

At present, researchers have developed a variety of nano-agents with NIR-II PTT properties. By encapsulating CT drugs, targeted transportation or in situ injection into tumor sites, the drugs are accurately released under the conditions of NIR-II laser^319–325 or low pH,^238,326 which greatly improved the safety and efficiency of CT. Lan et al. developed an “all-in-one” nanoplatform that integrated at the NIR-II window dye IR1061 and anticancer drug paclitaxel (PTX) into an apoferritin (AFN) nanocage (IR-AFN@PTX) (Fig. 19a and b).³²⁷ Remarkably, 78.6% of PTX was released under acidic conditions (pH 5.0) with NIR-II laser irradiation, significantly more than the 3.2% released at physiological pH 7.4 (Fig. 19c). Deng et al. constructed Au nanostar@ZIF-8 (Au@MOF) nanoparticles, which encapsulated the DOX (Fig. 19d).¹³⁷ Upon exposured to the 1064 nm laser irradiation, the heat generated led to the dissociation of the Zn–O coordination within ZIF-8, doubling the release rate of DOX compared to conditions without irradiation (Fig. 19e). Shen et al. crafted thermosensitive liposomes (DG@TLs) activated by NIR-II (1064 nm) light, which encapsulated gambogic acid (GA).³²⁸ These liposomes leveraged a phase transition in the phase change materials (PCMs) from solid to liquid under hyperthermia induced by NIR-II PTT, facilitating controlled release of GA (Fig. 19f and g). The released GA enhanced the efficacy of NIR-II PTT by inhibiting HSP90 activity, reducing tumor thermoresistance and displaying potent chemotherapeutic effects, thus achieving a synergistic anti-tumor impact.

Fig. 19 (a) The preparation and application of IR-AFN@PTX-FA. (b) The scheme of pH/NIR-II responded drug release and heat generation. (c) Release kinetics of PTX from IR-AFN@PTX-FA.³²⁷ Reproduced with permission from ref. 327. Copyright 2021 Dove Medical Press. (d) The fabrication process and application of Au@MOF-DOX. (e) The viability rate of L929 cells incubated with Au@MOF at various Au concentrations.¹³⁷ Reproduced with permission from ref. 137. Copyright 2019 American Chemical Society. (f) Synthesis of DG@TLs and its anti-tumor therapy. (g) Cumulative GA release from DG@TLs under 1064 nm laser.³²⁸ Reproduced with permission from ref. 328. Copyright 2021 Royal Society of Chemistry.

Currently, encasing or loading CT prodrugs on nano-agents is a more advanced technological approach, which can be then transformed into CT drugs under NIR-II laser/TME. In this way, CT drugs can be transformed into effective molecular structures or drug monomers only at tumor site, which is more intelligent and avoids the toxicity of long-term circulation in the body. Cisplatin is the most commonly used CT drug in clinic and experiment, but its severe dose-limiting toxicity and drug resistance have greatly hindered its wider application. Tetravalent cisplatin (cispt(IV)) prodrug can be reduced by over-expressed GSH in TME and activated into more toxic cispt(II).³²⁹ Hyperthermia promotes the metabolism of cancer cells, thus further improving the intake of CT drugs. At present, numerous NIR-II PTT nanocarriers are employed for delivering cisplatin prodrugs for tumor treatment, such as ultrasmall CuS-modified Fe(III)-metal–organic frameworks (MIL-88),³³⁰ Pt(IV)-initiated photo-polymerized methacrylate gelatin (GelMA)-based hydrogel microparticles,³³¹ NIR-II light excitable photothermal lipid NPs (Fig. 20a).³³² Additionally, disulfiram (DSF) combined with Cu²⁺ is used in antitumor therapies. In the physiological environment, DSF is quickly metabolized into diethyldithiocarbamate (DTC), which forms a complex with Cu²⁺-bis (N,N-diethyldithiocarbamate) (Cu(DTC)₂). This complex has been utilized in photonic hyperthermia to enhance DSF-initiated cancer CT (Fig. 20b).³³³ In addition, there are some strategies to realize tumor treatment by cutting off covalent bonds and releasing CT drugs under NIR-II laser. Lu et al. reported that co-encapsulating of the redox-responsive prodrug camptothecin-combretastatin A4 (CPT-CA4) with the DPP-BT-TPA dye.³³⁴ These NPs were specifically designed to respond to the high levels of GSH in the TME, facilitating the release of the CT drug (CPT) and the angiogenesis inhibitor CA4 (Fig. 20c). This release process could be expedited by elevated temperatures, utilizing laser-induced hyperthermia to control drug release and boost therapeutic outcomes. Zhu et al. developed a versatile nanoplatform that enhanced CT with phototherapy, encapsulating a poly-prodrug (PEG–TPZ) inside the semiconducting polymer TDPP (Fig. 20d).³³⁵ The platform released tirapazamine (TPZ) by hydrolyzing the acrylamide bonds within the TME. This release triggered damage to blood vessels, which was then intensified by the hyperthermia produced during treatment.

Fig. 20 (a) The preparation of IRNPs-SBA/Pt IV and its mechanism for NIR-II FL-guided combined PTT and CT.³³² Reproduced with permission from ref. 332. Copyright 2023 Elsevier. (b) The fabrication of DSF@PEG-HCuSNPs and the corresponding synergy of PTT and CT.³³³ Reproduced with permission from ref. 333. Copyright 2021 American Chemical Society. (c) The fabrication process and drug release mechanism of DCssC NPs.³³⁴ Reproduced with permission from ref. 334. Copyright 2022 Elsevier. (d) The formulation of TDPP@PEG–TPZ and its applications.³³⁵ Reproduced with permission from ref. 335. Copyright 2023 Royal Society of Chemistry.

At present, a variety of CT drugs have transitioned from experimental research to clinical application, driven by the primary goal of benefiting cancer patients. The challenge of enhancing the effectiveness of these drugs while minimizing harm to normal cells remains a critical area of scientific inquiry. The integration of NIR-II PTT with CT drugs presents a promising solution. This combination therapy leverages the relative safety of mild PTT, additionally, it facilitates the controlled release of CT drugs or prodrugs, potentially improving treatment outcomes and minimizing side effects.

4.3.3 PTT and IO. PTT combined with IO has gradually become the mainstream cancer treatment measures in recent years. This is because, on one hand, relying solely on NIR-II PTT can lead to incomplete tumor ablation and potential recurrence, as tumor cells may activate self-protection mechanisms. On the other hand, traditional cancer immunotherapy methods—such as tumor vaccines and adjuvants, adoptive cell transfers, and immune checkpoint inhibitors—offer different mechanisms of action. This integrated therapeutic approach not only overcomes the limitations associated with using NIR-II PTT or immunotherapy separately but also enhances the overall efficacy of tumor treatment. By targeting cancer from multiple angles, this synergy could significantly reduce tumor resilience and recurrence, offering a robust framework for more effective cancer management.

Heat shock protein (HSP) are a diverse group of proteins found extensively in bacteria and mammals, synthesized in response to high temperatures to protect the organism.^336,337 Thus, the over-expression of HSP induced cell heat resistance will reduce the therapeutic effect of NIR-II PTT.^338,339 In IO, activated T cells can secrete TNF-α, a cytokine that reduces the expression of HSPs in tumor cells, thereby increasing their sensitivity to photothermal stimulation.^340,341 Yang et al. reported a NIR-II photothermal agent (BPBBT dots) coated with artificial dendritic cell (DC) membrane, this configuration preserved the antigen-presenting capability and enabled binding with endogenous T cells (Fig. 21a).³⁴² Consequently, it promoted TNF-α secretion by T cells and diminished HSP expression, significantly enhancing the efficacy of NIR-II PTT. Du et al. reasonably designed the nano-epigenetic therapeutic platform (GNR-siYTH1), which is consisted of a nuclear localization signal peptide-conjugated PEI-PLA polymer-coated gold nanorod and small interfering RNA targeting YTHDF1 (Fig. 21b).³⁴³ This platform decreased the translation of HSP70, which decreased the thermo-resistance of tumor cells and enhanced photothermal performance. Additionally, reducing ATP production in tumor cells disrupted the energy supply needed for HSP production, thereby diminishing the thermal resistance of tumors to NIR-II PTT (Fig. 21c).³⁴⁴ Wei et al. constructed a facile biomimetic nano-immunoactivator (CuS/Z@M4T1), by incorporating NIR-II photothermal agent CuS nanodots and 4T1 tumor cell membrane into a ZIF-8 structure (Fig. 21d).³⁴⁵ The overloaded Zn²⁺ lead to NAD depletion and systematic energy exhaustion by disrupting the metabolic processes, thus causing a reduction in intratumoral ATP levels, inhibiting HSP synthesis and enhancing the therapeutic efficacy of NIR-II PTT.

Fig. 21 (a) The preparation and assembly of DC@BPBBT dots and its imaging-guided PTT.³⁴² Reproduced with permission from ref. 342. Copyright 2022 John Wiley and Sons. (b) The preparation of N⁶-methyladenosine reader YTHDF1 siRNA loaded Au nanorods.³⁴³ Reproduced with permission from ref. 343. Copyright 2022 Elsevier. (c) Synthesis of Lip(DPQ + 2DG) NPs and its applications.³⁴⁴ Reproduced with permission from ref. 344. Copyright 2021 Elsevier. (d) The fabrication procedures and applications of the CuS/Z@M 4T1.³⁴⁵ Reproduced with permission from ref. 345. Copyright 2023 John Wiley and Sons.

The combination of NIR-II PTT and IO is a two-way promotion effect. In addition to reducing the expression of HSP and weakening the heat insensitivity of tumor cells, the heat generated by NIR-II PTT can improve the immunogenicity of tumors and create a favorable niche for tumor-infiltrating lymphocytes (TIL) recruitment, thus promoting the transformation of “cold” tumors (non-immunogenic tumors) into “hot” tumors (immunogens with increased T cell infiltration) in immune checkpoint blockade (ICB) therapy.^346–348 Wang et al. reported a AuPtAg-GOx nanozyme, which could produce mild PTT under 1064 nm laser and recruitment of TILs to reprogram the “cold” TME.³⁴⁹ Besides, the α-PD-L1 on the AuPtAg-GOx could effectively inhibit both primary and distant tumors, thus enhancing the potent tumor treatment capabilities of NIR-II PTT when combined with IO. Furthermore, NIR-II PTT can induce dying tumor cells to release tumor-associated antigens (TAAs), leading to immunogenic cell death (ICD) and thereby activating the immune response. At present, a range of nano-agents have been developed specifically for treating photothermal-induced immunogenic death, such as semiconducting polymer (SP) grafted with imiquimod R837 and indoximod IND (SPRIN-micelle),³⁵⁰ tumor cell membrane coated redox nanozyme (CMO-R@4T1),³⁵¹ semiconducting polymer nano engager (SPNE),³⁵² Ag@CuS-TPP@HA NPs,³⁵³ GdOF@PDA-HA-R837-hydrogel complex,³⁵⁴ theragnostic thermosensitive liposome (PLDD) which contained a multifunctional photothermal agent (DTTB) and an immune potentiator STING pathway agonist (DMXAA),³⁵⁵ NIR-II light-activated semiconducting polymer nano mediators (SPNaiB).³⁵⁶

This approach effectively facilitates the release of cellular contents and inflammatory cytokines, and enhances the anti-tumor immune response by synergizing with cell death induced by NIR-II PTT. The human immune system can leverage these effects to trigger a cascade of immune reactions, effectively eradicating tumor cells. This combination therapy offers benefits such as low side effects, lack of drug resistance, and broad-spectrum anti-cancer properties. Looking ahead, the development of various vaccine adjuvants that harness the NIR-II photothermal effect to prevent or treat tumor diseases represents a promising, well-tolerated, and effective treatment strategy for patients.

5. Challenges and future prospects

Although NIR-II optical imaging and phototherapy hold great potential, they face several challenges. The complexity of biological tissues—affected by factors such as absorption, scattering, and blood content—may hinder the effectiveness of NIR-II imaging and treatment. Furthermore, the stability and biocompatibility of nano-agents, which are crucial for NIR-II diagnostics and therapy, need enhancement to avoid immune reactions or tissue damage. Additionally, accurately targeting nano-agents to lesions and finely tuning phototherapy performance to ensure safety and efficacy remain challenging.

In future development, researchers can improve the effectiveness of NIR-II optical diagnosis and treatment integration nanoplatforms in three main aspects: (1) design and optimization of nano-agents: by controlling their morphology, surface functionalization, and structural stability. Nano-agents can be tailored for targeted delivery and tracking, serving not only as precise diagnostic and therapeutic tools but also as drug carriers with controlled release capabilities. (2) By integrating NIR-II optical imaging with other modalities like MRI or CT and employing techniques such as biomarkers and immunohistochemical labeling, imaging accuracy and detail can be significantly improved, thus better guiding treatment planning and adjustment. (3) Precise control of NIR-II phototherapy temporal-spatial light response mechanism: developing optical-controlled drug release systems within the NIR-II window could enable precise drug delivery and phototherapy dose regulation, maximizing therapeutic outcomes while minimizing side effects.

Moreover, as NIR-II optical diagnosis and treatment integration nanoplatforms progress towards clinical application, creating personalized treatment plans represents a vital direction for future clinical transformation. By leveraging the deep tissue penetration of NIR-II light combined with the precision of localized phototherapy, personalized treatment plans can significantly enhance treatment efficacy and patient quality of life.

6. Conclusion

In summary, the construction of NIR-II optical diagnosis and treatment integration nanoplatforms using a variety of nano-agents with outstanding optical properties—such as high FL intensity, strong PA imaging signals, efficient PCE, significant ROS production, and targeted CT drug release—facilitates multiple phototherapy mechanisms guided by NIR-II FL and PA imaging. This approach substantially addresses the limitations of poor tissue penetration, high tissue absorption and scattering, and low spatial and temporal resolution associated with the visible and NIR-I windows. Consequently, this emerging platform will open new vistas of cancer diagnosis and treatment in the future.

Author contributions

Conceptualization, H.M. L., P.J. L., and H.Y. S.; visualization, H.M. L. and J.R. Z.; investigation, Z.Y. L., L.T. B.; methodology, H.M. L. and H.Y. S.; writing—original draft, H.M. L., P.J. L. and J.R. Z.; writing—review & editing, H.M. L. and H.Y. S. The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript.

Data availability

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

There are no conflicts to declare.

Acknowledgements

This work was supported by the Major Research Plan of the National Natural Science Foundation of China (92359202), the Beijing Natural Science Foundation (L212001), the National Natural Science Foundation of China (51972343).

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