Injectable hydrogel enabled by strained disulfide-thiol exchange and <?A3B2 pi6?>core-shell thiolated copolymer nanoparticles for efficient hydrophobic drug delivery

Injectable hydrogels formed via dynamic chemical crosslinks hold great promise as drug delivery platforms due to their robust yet adaptable nature, stimuli-responsiveness, and tunable structures and properties. However, their inherently high water content poses a significant challenge for the efficient encapsulation and sustained release of hydrophobic drugs. Here, we present a novel injectable hydrogel system constructed via a strain-promoted disulfide-thiol exchange between dithiolane-functionalized polymer strands and thiolated core-shell nanoparticles (NPs) under physiological conditions. The hydrophobic core and hydrophilic shell structure of the NPs enables effective loading and protection of hydrophobic drugs, while rapid gelation occurs upon mixing the thiolated NPs with dithiolane-polymers in phosphate-buffered saline. The hydrogel shows excellent injectability, self-healing capability, in vitro biodegradability, and cytocompatibility. This hydrogel system enables sustained release of hydrophobic drugs over 32 days in aqueous media and supports sequential dual-drug release. Its redox-responsiveness under tumor-mimicking reducing conditions, enabled by the disulfide crosslinks, further facilitates controlled intracellular drug release. This multi-component platform offers a versatile strategy for designing advanced injectable hydrogels with potential applications in hydrophobic drug delivery and other biomedical fields.