Design rules for externally triggered drug uncaging under optical and radiolytic regimes

Externally triggered prodrug activation can improve therapeutic index by decoupling systemic distribution from pharmacological activity. This review examines prodrug uncaging strategies enabled by electromagnetic radiation through the lens of activation physics and clinical constraints, spanning UV-visible-near-infrared photochemistry and ionizing radiation. Differences in clinical applicability arise from fundamentally contrasting activation physics and irradiation geometry. While recent reviews have cataloged externally triggered prodrug systems across multiple modalities, we instead organize the field by activation regime and evaluate these systems under clinically realistic constraints. In photochemical activation, direct light-chromophore coupling enables predictable bond cleavage through defined excited-state pathways, but effective application is constrained by tissue optics and beam-sample geometry. X- and γ-rays penetrate deeply into tissues, but their uncaging pathway is indirect via diffusible water radiolysis products, resulting in stochastic rather than deterministic cleavage chemistry. We evaluate these platforms using deliverability, irradiation geometry, dose efficiency under clinically realistic conditions, microenvironment dependence, and functional group compatibility. We conclude with practical design rules and a decision framework that aligns targeted pathology and treatment objectives with the appropriate trigger chemistry, payload selection, and delivery strategy under the governing activation physics.