Versatile smart hydrogels for spatiotemporal drug delivery to orchestrate diabetic bone regeneration

Hyperglycemia-induced oxidative stress accelerates bone senescence, presenting a major challenge for diabetic bone regeneration. In this study, we developed a smart hydrogel by crosslinking hyaluronic acid (HA) grafted with 3-aminophenylboronic acid (HA-PBA) and polyvinyl alcohol (PVA) via phenylboronic acid ester bonds, incorporating metformin (Met), and anchoring parathyroid hormone-related peptide-1 (PTHrP-1) onto polydopamine (PDA)–hybridized nanosized zeolitic imidazolate framework-8 (P1@PZIF-8) to improve the osteogenic microenvironment and repair diabetic bone defects. Incorporation of PZIF-8 shortened gelation time and enhanced the mechanical strength of the HPA hydrogel. The system enabled dynamic, spatiotemporal drug release: >80 % of Met was released within 12 days, while PTHrP-1 and Zn 2+ were released gradually over 28 days. This controlled release reduced reactive oxygen species (ROS) accumulation, maintained a favorable redox balance, promoted autophagy, prevented bone marrow mesenchymal stem cells (BMSCs) senescence, and enhanced osteogenesis. Additionally, it delayed high-glucose-induced endothelial cell senescence and improved pro-angiogenic activity. Transcriptome sequencing revealed that the hydrogel inhibited BMSCs senescence via the PI3K–AKT–mTOR pathway and promoted osteogenesis through the Wnt/β-catenin pathway. In vivo, it enhanced angiogenesis, osteogenesis, and tissue remodeling while reducing cellular senescence in diabetic bone defects. Thus, the spatiotemporally controlled drug-release platform thus provides a potent therapeutic strategy to accelerate bone regeneration and functional recovery in the diabetic milieu. A schematic illustration of the Met-PP-HPA hydrogel featuring spatiotemporally controlled drug release, which modulates oxidative stress to rejuvenate aging cell function and facilitate the repair of bone defects in diabetes. • Glucose/ROS-responsive hydrogel enables spatiotemporal drug release for diabetic bone repair. • Rapid Met release combats aging early; sustained PTHrP-1/Zn 2+ release promotes long-term osteogenesis. • PDA/ZIF-8 hybrid carriers boost drug load & hydrogel mechanics via phenol-borate crosslinking. • Synergistic “antioxidant-anti-aging-osteogenesis” cascade accelerates diabetic bone regeneration.