Natural Photosensitizers in Cancer Therapy: A Chemo-Biodiversity Perspective on Light-Activated Natural Compounds

Natural photosensitizers have emerged as promising candidates for photodynamic therapy (PDT) owing to their structural diversity, favorable biocompatibility, and broad biological activities. However, their significance extends beyond their natural origin, as they represent the products of chemo-biodiversity shaped by millions of years of evolutionary adaptation to diverse ecological pressures. This review examines natural photosensitizers through a chemo-biodiversity perspective, emphasizing how evolutionary diversification has generated structurally distinct photoactive scaffolds with unique photophysical and photobiological properties relevant to cancer therapy. Attention is given to the relationships between molecular architecture, excited-state dynamics, reactive oxygen species generation, and therapeutic performance, highlighting how structural features govern photodynamic efficiency and biological responses. The review further discusses how nanotechnology-based engineering strategies can overcome intrinsic limitations, including poor aqueous solubility, aggregation, photoinstability, and limited tumor selectivity. Recent advances in multifunctional nanoplatforms, molecular engineering, and combination therapies are critically evaluated alongside current translational challenges, including manufacturing, regulatory considerations, and clinical development. By integrating natural product chemistry, photophysics, photobiology, and nanotechnology within a unified conceptual framework, this review demonstrates that chemo-biodiversity provides a rational foundation for the discovery of next-generation natural photosensitizers. Harnessing nature's evolutionary molecular diversity offers new opportunities to develop safer, more effective, and clinically translatable photodynamic therapies.