Crosslinker-Integrated Photocleavable Gelatin–PEG Hydrogel via Bioorthogonal SPAAC Chemistry for UV-Triggered On-Demand Degradation

Light-triggered hydrogel systems offer precise spatiotemporal control over drug release, yet most existing approaches require direct chemical conjugation of a photocleavable linker to the payload, which risks compromising bioactivity and limits applicability to structurally diverse molecules. Here, we report a gelatin–poly(ethylene glycol) (PEG) hybrid hydrogel crosslinked via strain-promoted azide–alkyne cycloaddition (SPAAC) click chemistry, in which an o-nitrobenzyl photocleavable (PC) linker is incorporated into the PEG crosslinker arm rather than conjugated to the drug. Acetylated gelatin–azide (AGA) was synthesized by sequential azide functionalization and amine capping of gelatin, and four-arm PEG-PC-DBCO (4armPEG-PC-DBCO) was prepared by coupling a PC DBCO-PEG4-NHS ester to four-arm PEG amine. Successful incorporation of the azide, DBCO, and o-nitrobenzyl moieties was confirmed by FT-IR spectroscopy, 1H NMR spectroscopy, and UV-Vis spectrophotometry. Hydrogel formation under physiological conditions (PBS, 37 °C) without catalysts or initiators was verified by rheological frequency sweep analysis, which confirmed elastic-dominant behavior (G′ > G″). Upon irradiation at 365 nm, the crosslinker was cleaved, and rapid network dissolution was observed both macroscopically and by in situ time sweep rheology. This platform enables on-demand, UV-selective hydrogel degradation independently of payload identity, providing a versatile foundation for future controlled drug release applications and dynamic, on-demand degradable scaffolds for tissue engineering.