A microenvironment-responsive hydrogel biointerface for targeted inhibition of RIPK1-dependent programmed cell death...

Diabetic chronic nonhealing wounds are characterized by persistent inflammation, oxidative stress, and impaired tissue regeneration, which are closely associated with receptor-interacting serine/threonine-protein kinase 1 (RIPK1)-mediated programmed cell death. Although RIPK1 kinase represents a promising therapeutic target, its role in diabetic wound healing and effective local delivery strategies remain largely unexplored. Here, we report a local therapeutic system for diabetic wound healing, RIPK1i@PTM/TA, based on a pH/glucose dual-responsive hydrogel biointerface rationally designed to adapt to the pathological wound microenvironment. The hydrogel is constructed from a poly(acrylic acid)-terminal-olefin polyethylene glycol ether-phenylboronic acid copolymer (PTM) and dynamically crosslinked with tannic acid (TA), endowing the network with microenvironment-sensitive structural modulation, tissue adhesion, and antibacterial functionality. RIPK1 inhibitor is stably immobilized within the reversible crosslinked matrix, enabling localized, on-demand, and sustained drug release at the wound-material interface in response to acidic pH and elevated glucose levels. Functionally, RIPK1i@PTM/TA enhanced fibroblast activity in vitro, and in diabetic chronic wound mouse models effectively suppressed RIPK1-dependent cell death, alleviated inflammation and oxidative stress, and promoted angiogenesis, ultimately accelerating wound closure and structural reconstruction. Collectively, this study demonstrates an effective microenvironment-responsive hydrogel for topical drug delivery in refractory diabetic wounds.