Bidirectional integrin β1 activation synergizes neurovascular coupling and enhances bone regeneration.

Reconstruction of large segmental bone defects remains challenging because current grafting strategies often fail to coordinate angiogenesis, neurogenesis, and osteogenesis. Here we developed a functional scaffold (peptide/Talin1 plasmid/PLA-HA/GelMA, PTPG) capable of simultaneously delivering peptides and Talin1 plasmids. We hypothesized that this scaffold enables neurovascularized bone regeneration through bidirectional activation of integrin β1 (ITGB1). The REDV-IKVAV (Arg-Glu-Asp-Val-Gly-Gly-Gly-Ile-Lys-Val-Ala-Val) peptide triggers "outside-in" ITGB1 signaling in endothelial and Schwann cells, while Talin1 plasmid-mediated "inside-out" activation. This PTPG scaffold synergistically enhances cell proliferation, migration and secretion, which are eliminated by ITGB1 silencing. In vivo, PTPG scaffold promotes aligned neurovascular networks guiding bone deposition. Single-cell RNA sequencing demonstrates enrichment of endothelial H-type signatures and repair-associated Schwann cell phenotypes, with activation of ITGB1-focal adhesion kinase-paxillin signaling. Collectively, this scaffold integrates structural support with peptide and genetic cues to promote coordinated angiogenesis, neurogenesis, and osteogenesis, offering a promising strategy for functional bone regeneration.