In situ forming ROS-scavenging hydrogel with STING inhibitor delivery promotes bone mesenchymal stem cells osteogenic differentiation via regulating macrophage M2 polarization

Bone regeneration is frequently impaired by excessive reactive oxygen species (ROS) and prolonged inflammation, which disrupt the immune microenvironment and hinder osteogenesis. The stimulator of interferon gene (STING) pathway is an innate immune pathway and a critical mediator of the inflammatory response, has been increasingly implicated in inflammatory bone loss and impaired repair. While STING inhibition represents a promising therapeutic strategy, its effective implementation within the bone microenvironment requires spatiotemporally controlled delivery. Here, we developed an injectable and photocrosslinkable hydrogel system (GMPP+H151) that integrates ROS-responsive scavenging with targeted STING inhibition to synergistically guide immune microenvironment remodeling and bone regeneration. The GMPP hydrogel was fabricated through dual crosslinking of phenylboronic acid (PBA)-modified gelatin (GelMA) and polyvinyl alcohol (PVA), endowing it with self-healing properties and ROS-scavenging capacity. H151, a small molecule inhibitor of STING, was caged by PBA chemistry for on-demand release under oxidative stress. The GMPP+H151 can significantly reduce ROS levels in macrophages and promote their phenotypic differentiation from M1 to M2 by suppressing the STING pathway, downregulating pro-inflammatory cytokines, and upregulating anti-inflammatory factors. Furthermore, it efficiently enhanced survival, spreading, and osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs), leading to increased expression of alkaline phosphatase (ALP), runt-related transcription factor 2 (RUNX2), and osteocalcin (OCN). This study presents a smart, multifunctional hydrogel drug delivery system that integrates immunomodulation and osteoinduction, offering a promising strategy for promoting osteogenic differentiation and in situ bone defect repair.