Photocage Prodrug Coupled with Injectable Hydrogel for Self-Amplified Photochemotherapy

Developing photocages within the phototherapeutic window is crucial for efficient photopharmacology regulation, yet it poses significant challenges. Herein, we present a photocage prodrug of doxorubicin-methylene blue (DOX-MB) linked by a urea bond, offering spatiotemporal therapeutic selectivity and reduced systemic toxicity. In particular, this photocage prodrug remains stable under physiological conditions, exhibiting reduced cytotoxicity and quenched fluorescence. Upon 660 nm laser irradiation, DOX-MB generates reactive oxygen species that selectively cleave the urea linkage, facilitating the concurrent release of an active pharmaceutical ingredient. This photoactivatable cleavage of DOX-MB allows for precise chemotherapy and photodynamic therapy and restores MB FL for real-time monitoring as well. To achieve localized tumor therapy, the DOX-MB prodrug was encapsulated into a thermosensitive hydrogel, further minimizing the systemic exposure. In vivo studies showed that this integrated platform achieved a tumor inhibition rate of 80.3%. Collectively, this study presents a precision-engineered photoactivatable prodrug that enables synergistic photochemotherapy.