A bioinspired adhesive hydrogel promotes bone regeneration through osteoimmunomodulation and angiogenic-osteogenic coupling.

Delayed bone defect repair is mainly attributed to insufficient mechanical interlocking between the material and host tissue, excessive inflammation, and inadequate vascularization. Here, we report a bioinspired organic-inorganic composite hydrogel (OP/bECM@Z) developed based on the biphasic structure of native bone. Phenylboronic acid-modified oxidized alginate (OP) self-assembles into a dynamic, injectable, tissue-adhesive network; decellularized bone extracellular matrix (bECM) serves as a biomimetic analog of the organic phase, supporting cell adhesion, migration, and osteogenesis; ZIF-8 affords sustained Zn2+ release and mechanical reinforcement, thus emulating the mineral phase. The scaffold provides robust tissue adhesion and sustained release of bioactive factors, including TGF-β, VEGF, Zn2+, and osteogenic cues, thereby modulating the immune microenvironment and facilitating angiogenesis and osteogenesis. In vitro, OP/bECM@Z inhibits M1 macrophage polarization while promoting M2 polarization, enhances HUVEC migration and tube formation, and stimulates BMSC proliferation and osteogenic differentiation. In vivo, it significantly accelerates bone regeneration, collagen deposition, and neovascularization in a rat cranial defect model. Mechanistically, its pro-osteogenic effects involve activation of the Rap1 signaling pathway. Collectively, OP/bECM@Z provides an "anti-inflammatory-pro-angiogenic-pro-osteogenic" strategy, offering a promising bioadhesive platform for the repair of critical-sized bone defects and offering new insights into the design of biomimetic bone regenerative materials.