Shi‐Yao Guo, Mingyue Zhang, Ke Zhang, Xiaotong Lu, Peiran Chen, Bangliu Yang, Xueqian Wang, Yuhong Zhuo, Dongqin Yu, Chao Qi, Kaiyong Cai
Abstract Osteoporosis compromises bone repair by generating a dysregulated microenvironment marked by excessive accumulation of reactive oxygen species (ROS) and a reduced pH. This pathological state leads to mitochondrial dysfunction, impaired osteogenic differentiation, and excessive activation of osteoclasts. In this study, a ROS‐responsive titanium implant coating composed of calcium carbonate‐mineralized nicotinamide mononucleotide (NMN) nanoparticles, lipoic acid‐modified gelatin (LAMG), and sodium alginate (SA) is developed, designed to enhance osseointegration through dual synergistic mechanisms. First, the LAMG hydrogel effectively scavenges excess ROS, while calcium carbonate neutralizes H + ions and restores physiological pH levels, thereby reducing acid‐induced bone resorption and inhibiting osteoclast activity. Second, ROS and H + ions‐triggered release of NMN enhances the intracellular NAD⁺/NADH ratio in bone marrow mesenchymal stem cells, activates the SIRT1 signaling pathway, restores mitochondrial function, and promotes osteogenic differentiation. By concurrently remodeling the pathological bone microenvironment and repairing mitochondrial dysfunction, this multifunctional coating suppresses osteoclast‐mediated bone resorption while facilitating osteoblast formation, thereby enhancing peri‐implant osseointegration under osteoporotic conditions. This strategy not only presents a promising therapeutic approach for functionalizing titanium implants but also offers a potentially translatable platform for treating osteoporotic bone defects.