Dual immuno-mechanical programming of a biomimetic periosteum for load-bearing bone restoration.

Age-related cortical bone loss remains a major clinical challenge, as current interventions largely neglect the load-bearing cortex and its periosteal niche. Here, a dual-targeted biomimetic periosteum is engineered by mechanistically decoding how inflammaging and mechanical decline converge to impair periosteal stem/progenitor cell (PSC) function. Aging-associated macrophage polarization toward a pro-inflammatory M1 state suppresses Piezo1 expression in PSCs, whereas reduced mechanical input attenuates Piezo1 activation, jointly leading to defective mechanotransduction and osteogenesis. Guided by this mechanoinflammatory framework, a periosteum-mimetic membrane is rationally designed with two complementary modules. First, 2-N,6-O-sulfated chitosan (26SCS) is incorporated to repolarize macrophages and restore Piezo1 expression in PSCs. Second, electrospun fiber architecture is optimized to identify a diameter range that maximally activates Piezo1-dependent Ca2+ influx and YAP signaling under reduced mechanical conditions. This coordinated immunomodulatory-mechanosensory strategy reinstates PSC osteogenic competence and enhances cortical bone thickness and strength in aged and hindlimb-unloaded models. The regenerative effect is abolished in Prrx1+ Piezo1-deficient mice, confirming the necessity of Piezo1-mediated mechanotransduction. This work integrates immune microenvironment regulation with cell-scale mechanosensitive activation, providing a periosteum-targeted biomaterial strategy for rebuilding load-bearing cortical bone during aging and mechanical disuse.