Harnessing photo-chemoresponse for precise drug activation

Photo-chemoresponsive controlled drug delivery enables spatiotemporally precise interventions by transducing optical stimuli into defined drug activation events, overcoming the inability of conventional formulations to synchronize therapeutic action with disease dynamics. Covalent prodrug strategies utilizing photoresponsive protecting groups or coordinating ligands offer distinct advantages over physical encapsulation by ensuring exceptional chemical selectivity and pharmacological fidelity, thereby confining activation to illuminated lesions while mitigating off-target toxicity and acquired resistance. This review systematically examines the molecular design principles underlying six key photochemical mechanisms, including photoreduction, photocleavage, photoactivated ligand effects, photodynamic action, photothermal conversion, and synergistic pathways. Furthermore, we critically evaluate recent advances in the engineering of photo-chemoresponsive prodrugs, together with their inherent limitations and translational challenges, and discuss future directions for clinical implementation. By providing a comprehensive overview of these mechanisms and strategies, this review serves as a valuable reference for the rational design of next-generation precision phototherapeutics.