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Gene therapy targeting BMSCs is emerging as a promising strategy to promote fracture healing. However, the oxidative stress and mitochondrial dysfunction in BMSCs considerably weaken the efficacy of gene therapy. In this study, an intelligent gene delivery system is engineered for targeted gene delivery to BMSCs, utilizing diselenide\u2010bridged mesoporous organosilica nanoparticles (SeMONs) modified with a BMSC\u2010affinity peptide (E7). Compared to conventional mesoporous organosilica nanoparticles, SeMONs exhibit not only superior gene delivery properties but also unique reactive oxygen species (ROS)\u2010responsive degradation and scavenging capabilities. Given that siRNA\u2010Foxf1 (siFoxf1) is known to promote osteogenesis, this gene delivery system carrying siFoxf1 (E7\u2010SeMONs@siFoxf1) is anchored onto metal implants, to create a novel coating designed to promote fracture repair. In vitro, E7\u2010SeMONs@siFoxf1 synergistically promoted BMSCs osteogenesis by restoring mitochondrial homeostasis and upregulating osteogenic gene expression. In vivo, metal implants coated with E7\u2010SeMONs@siFoxf1 significantly accelerated rat femoral fracture healing. Transcriptome sequencing further revealed that E7\u2010SeMONs@siFoxf1 promotes osteogenesis primarily by activating the PI3K\/Akt\/GSK3\u03b2\/\u03b2\u2010catenin pathway. This study introduces an innovative strategy that combines gene therapy with mitochondrial homeostasis regulation for fracture treatment, demonstrating promising clinical prospect.<\/jats:p>","DOI":"10.1002\/adhm.202501411","type":"journal-article","created":{"date-parts":[[2025,6,13]],"date-time":"2025-06-13T01:30:59Z","timestamp":1749778259000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Intelligent Gene Delivery System Functionalized Metal Implants for Fracture Repair via Remodeling Mitochondrial Homeostasis"],"prefix":"10.1002","volume":"14","author":[{"given":"Gang","family":"Zheng","sequence":"first","affiliation":[{"name":"Department of Orthopedics Shanghai Changzheng Hospital Second Affiliated Hospital of Naval Medical University  Shanghai 200003 P. R. 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