A dual-crosslinked hydrogel with time-sequential drug release for stage-specific therapy of corneal alkali burns

• An in situ-forming, dual-crosslinked hydrogel is developed to provide mechanical support and time-programmed drug delivery for corneal alkali burns. • The hydrogel achieves stage-adapted therapy: rapid release of dexamethasone phosphate suppresses early inflammation, while sustained glycyrrhizin release from PLGA nanoparticles counteracts later fibrosis. • The sequential drug release potently inhibits the HMGB1–NF-κB–IL-1β signaling axis, effectively uncoupling inflammation from fibrosis. • This strategy significantly promotes corneal epithelial regeneration, restores transparency, and reduces fibrotic scarring in vivo. Corneal alkali burns rank among the most severe ocular injuries, characterized by a dynamically evolving pathology that requires distinct therapeutic strategies at different stages—a critical challenge that conventional static drug delivery systems fail to address. To overcome this limitation, we developed an in situ-forming dual-crosslinked hydrogel (AlgMA/GelMA) capable of time-sequential drug release for stage-specific pharmacotherapy. It was engineered to release dexamethasone phosphate (Dex-P) rapidly to control acute inflammation, followed by sustained release of glycyrrhizin (Gly) encapsulated in PLGA nanoparticles (NPs). This design not only circumvents the ocular side effects associated with long-term glucocorticoid use but also targets HMGB1 to suppress the pro-fibrotic inflammation–fibrosis axis. In vivo studies demonstrated that this sequential release system significantly accelerated corneal epithelial regeneration, restored corneal transparency, and suppressed key inflammatory pathways. Mechanistic investigations revealed that the coordinated action of Dex-P and Gly potently suppresses the HMGB1–NF-κB–IL-1β pathway, thereby effectively attenuating both inflammatory and fibrotic cascades. This study establishes a versatile, pathophysiology-driven material platform, proposing a new paradigm for treating multi-stage ocular diseases and tissue injuries.