Enhancing Photodynamic Therapy for Cancer: A Two-Photon Excited Approach with a Novel Mitochondrial-Targeted Photosensitizer

Abstract

Photodynamic therapy (PDT) has emerged as a non-invasive and safe cancer treatment owing to its excellent control, high selectivity, minimal systemic toxicity, and low drug resistance, contrasting sharply with conventional treatments such as chemotherapy, radiotherapy, and surgery. Two-photon PDT has garnered significant interest in the biomedical field for its ability to activate photosensitizers by simultaneously absorbing two near-infrared (NIR) photons. Distinguished from one-photon excited PDT, two-photon excited PDT (TPE-PDT) utilizes two NIR photons for excitation, offering increased tissue penetration, improved spatial resolution, reduced background fluorescence, and decreased photodamage and photobleaching. These advantages make it highly beneficial for tumor treatment. Developing novel TPE-PDT strategies that feature long emission wavelengths, robust light stability, and subcellular organelle targeting is a challenging. This study introduces a mitochondrial targeting TPE-PDT scheme based on aggregation-induced emission properties. The nanoparticles demonstrated highly specific mitochondrial targeting. These nanoparticles efficiently generated reactive oxygen species upon exposure to an 830-nm femtosecond laser. This activates the GSDME pyroptosis pathway, leading to effective tumor cell eradication. Hence, this study presents an innovative therapy approach that significantly enhances the efficacy of PDT, making it a possible contender for cancer therapy in translational nanomedicine.