Tumor Microenvironment-Modulated Self-illuminating Photodynamic Therapy: A Promising Tool for Deep-Seated and...

Due to its noninvasiveness and high spatiotemporal selectivity, photodynamic therapy has been used clinically to treat superficial tumors for decades. However, the low tissue penetration of external excitation light makes it ineffective against deep-seated tumors and metastases. To fundamentally address this limitation, laser-free self-illuminating photodynamic therapy using internal light sources has emerged as a potential solution. It involves the use of platforms that are driven either through oxidative chemical excitation, such as chemiluminescence and bioluminescence, or radiological excitation from β-emitting isotopes in the form of Cherenkov luminescence. The electronic excitations generated are then transferred to the photosensitizers by different energy transfer mechanisms. This review offers a thorough overview of recent progress in self-illuminating PDT technologies, focusing on key energy transfer mechanisms such as resonance energy transfer, chemically induced electron exchange luminescence, and Cherenkov radiation energy transfer. We have used contemporary examples from the literature and critically analyzed the aspects that make these platforms successful as compared to conventional systems. In the end, we have presented a brief discussion on the current challenges with remedial measures and future perspectives of self-illuminating photodynamic therapy, which will help researchers to design new innovative internal light sources to overcome the major limitation of photodynamic therapy and further expand its application to deep-seated and metastatic tumors.