Photocatalysis in Living Systems: From Photocatalytic Chemistry to Biological Applications

Photocatalysis has emerged as a powerful strategy for driving non-native, bioorthogonal transformations in living systems with stringent optical gating and spatial restriction. By converting photon energy into single-electron transfer (SET) or energy transfer (EnT) manifolds, photocatalysts can activate silent functional handles to generate transient, highly reactive species, including nitrogen-centered radicals, nitrenes, ketenimines, carbenes, quinone methides, and reactive oxygen species, under physiologically relevant conditions. In this review, we establish an integrated chemical biology framework that unifies reactive warheads, photophysical activation modes, and spatial-reach dynamics with downstream biological functions. We systematically categorize major photocatalytic reaction manifolds according to the warheads, reaction types, and biological applications, covering aryl azide photoredox activation, carbene generation from diazirines and diazo precursors, bioorthogonal deprotections, ROS photogeneration, and in situ chemical programming. Furthermore, we evaluate how these fundamental reaction manifolds overcome long-standing biological bottlenecks in high-resolution proximity labeling, hypoxia-tolerant phototherapy, and logic-gated prodrug uncaging, as well as emerging intracellular synthesis and polymerization. Finally, we conclude with a critical outlook on photophysical dosimetry, modular targeting architectures, quantitative spatial calibration, and translational challenges, providing a clear roadmap for the rational design and execution of photocatalytic chemistry in complex living biological systems.