Wentao Wang, Zhenyu Li, Siming Zhang, Yue Ma, Lei Yu, Qidong Zhang, Guoqing Pan, Dechun Geng, Chen Zhu, Jiaxiang Bai
Abstract The reduced initial stability of orthopedic implants in osteoporotic bone matrices, coupled with excessive M1 macrophage polarization at bone‐implant interfaces, disrupt bone–immune homeostasis and vascularization, ultimately leading to implant loosening or failure. Inspired by the marine mussel Mytilus edulis foot protein (Mefp), a pH‐responsive multifunctional bone glue (YDC‐Gel‐Zn) with broad‐spectrum adhesion capabilities is developed for osteoporotic bone‐implant integration. This pseudo‐Mefp bioglue enables dual‐interface adhesion via catechol‐rich sequences that mediate stable metal‐phenolic coordination with metallic implants and hydrogen‐bonded/Michael addition‐driven interactions with the bone matrix, thereby improving initial implant fixation. Under osteoporotic inflammatory microenvironments, sequential dissociation of borate ester bonds and metal‒phenolic coordination facilitates the controlled release of Zn 2 ⁺ and proangiogenic/osteogenic peptides (YDC). The released Zn 2 ⁺ remodels glutathione metabolism through glutathione S‐transferase (GST)‐mediated regulation of glutathione (GSH) levels, inhibits JAK1/STAT1/NLRP3 inflammasome activation, and suppresses the release of proinflammatory cytokines from senescent M1 macrophages, recalibrating the osteo‐vascular‐immune microenvironment. Due to its positive effects on bone regeneration and angiogenesis, the bioinspired bone bioglue demonstrated a 194% increase in fixation strength in osteoporotic rat models, achieving 93% healthy bone‐implant stability. Overall, this study provides a clinically translatable strategy for stable implantation under osteoporotic conditions through synergistic mechanical adaptation, bioactivity regulation, and smart environmental responsiveness.