Rethinking photosensitization in therapy and sun protection.

Light-induced tissue damage involves photosensitization. This process forms the basis of photodynamic therapy but also underlies photoaging and skin cancer development during excessive sun exposure. This review bridges these interlinked, yet rarely connected fields. We propose a unified classification distinguishing photosensitizers, photocatalysts, photoinitiators, and photocatalytic initiators based on absorber fate and downstream radical chain propagation. This framework resolves longstanding ambiguities and carries direct mechanistic consequences. Our central thesis is that subcellular localization determines the biological outcome far more than quantum yields. Membrane-bound photosensitizers permeabilize organelles orders of magnitude more efficiently than their broadly distributed counterparts, provided direct photosensitizer-lipid contact favors truncated lipid generation through Type I electron-transfer reactions rather than singlet oxygen oxidation. Organelle-specific targeting exploits this principle. Mitochondrial photodamage triggers regulated cell death through cardiolipin oxidation and cytochrome c release. Lysosomal targeting induces cathepsin release and autophagy dysfunction, often proving more effective for long-term cell killing. Dual-organelle strategies activate apoptosis, ferroptosis, and pyroptosis synergistically. These same mechanisms operate during sun exposure. Lipofuscin mediates radical chain amplification, creating a feed-forward cycle of visible light sensitivity in aging skin. Pheomelanin acts as a Type I photosensitizer generating superoxide and hydrogen peroxide under visible light, while eumelanin dissipates photon energy as heat. The amplification inherent in photoinitiated processes explains why modest light doses overwhelm antioxidant defenses, tipping redox homeostasis from eustress to distress. We translate these insights into mechanistically rational photoprotection strategies addressing visible light beyond conventional UV filters and into design principles for next-generation therapeutic photosensitizers.