Intelligent Gene Delivery System Functionalized Metal Implants for Fracture Repair via Remodeling Mitochondrial Homeostasis

Abstract Delayed union and nonunion of fractures are primarily attributed to the impaired osteogenic activities of bone marrow mesenchymal stem cells (BMSCs). 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‐bridged mesoporous organosilica nanoparticles (SeMONs) modified with a BMSC‐affinity peptide (E7). Compared to conventional mesoporous organosilica nanoparticles, SeMONs exhibit not only superior gene delivery properties but also unique reactive oxygen species (ROS)‐responsive degradation and scavenging capabilities. Given that siRNA‐Foxf1 (siFoxf1) is known to promote osteogenesis, this gene delivery system carrying siFoxf1 (E7‐SeMONs@siFoxf1) is anchored onto metal implants, to create a novel coating designed to promote fracture repair. In vitro, E7‐SeMONs@siFoxf1 synergistically promoted BMSCs osteogenesis by restoring mitochondrial homeostasis and upregulating osteogenic gene expression. In vivo, metal implants coated with E7‐SeMONs@siFoxf1 significantly accelerated rat femoral fracture healing. Transcriptome sequencing further revealed that E7‐SeMONs@siFoxf1 promotes osteogenesis primarily by activating the PI3K/Akt/GSK3β/β‐catenin pathway. This study introduces an innovative strategy that combines gene therapy with mitochondrial homeostasis regulation for fracture treatment, demonstrating promising clinical prospect.