Targeted Macrophage Metabolic Reprogramming In Osteoporotic Mandibular Defects

This project aims to utilize advanced nanomaterials and RNA interference technology to target and regulate macrophage metabolic reprogramming, inhibit HIF-1α-mediated histone lysine lactylation modification in macrophages, promote the phenotypic switching of macrophages, thereby inhibiting osteoclast activation, and ultimately enhance the regenerative repair of OMD Osteoporotic mandibular defects were created in ovariectomized mice, with bone metabolism tracked via micro-CT, histology, and cytokine assays. Calcium phosphate nanoparticles (HIF-NPs) loaded with HIF-1α siRNA and dual-modified with hyaluronic acid (HA) and folic acid were developed for macrophage-targeted delivery. In vivo efficacy was evaluated by BMD, bone microstructure, and metabolic markers post-IV injection. In vitro studies on macrophages/osteoclasts assessed HIF-NPs' effects on polarization, glycolysis, and lactate metabolism. RNA-seq identified key genes , MCT and HBO1, validated via molecular assays, to elucidate mechanisms underlying HIF-NPs-mediated repair. HIF-1α orchestrates macrophage metabolic reprogramming in hypoxic/inflammatory bone microenvironments, enhancing glycolysis and lactate secretion. Lactate triggers histone lactylation at osteoclastogenic gene loci, amplifying bone resorption. HIF-NPs effectively silenced HIF-1α, reducing macrophage glycolysis and lactate production, attenuating pro-inflammatory cytokine cascades, and suppressing osteoclast differentiation. This disrupted the pathological feedback loop between inflammation, hypoxia, and bone destruction, restoring osteoblastic activity. By dissecting the HIF-1α-lactylation axis in OMD pathogenesis, this work demonstrates that nanoparticle-mediated RNAi can reprogram macrophage metabolism to resolve inflammatory/hypoxic microenvironments, offering a precision therapeutic strategy for osteoporosis-associated bone defects with translational potential.