Tfna/Rapamycin Targets Cgas-Sting To Alleviate Senile Osteoporosis

This study examines the therapeutic effects of tFNA/Rapamycin nanocomplexes on senile osteoporosis by targeting the cGAS-STING pathway. Senile osteoporotic femoral defects were modeled in 4-month-old SAMP1 and SAMP6 male mice, which were divided into five groups (n=8 per group). Bone regeneration was evaluated by micro-CT, histological analyses (HE and Masson staining), and immunofluorescence of osteogenic factors and cGAS-STING pathway proteins. In vitro, BMSCs were senesced by induction and treated with tFNA, Rapamycin, or tFNA/Rapamycin nanocomplexes. Cellular senescence and osteogenic differentiation were assessed via β-galactosidase, ALP, and ARS staining. RT-qPCR, Western Blot, and immunofluorescence were used to detect senescence markers, osteogenesis-related indicators, and cGAS-STING pathway molecules. Statistical analysis was performed using one-way ANOVA (p<0.05). tFNA/Rapamycin significantly promoted bone defect healing in aged osteoporotic mice, upregulated RUNX2 and Osterix expression at the defect site, and suppressed key proteins of the cGAS-STING pathway. Cellular rejuvenation was achieved by simultaneously mitigating BMSC senescence and cGAS-STING overactivation, which restored osteogenic factor expression and showed greater therapeutic efficacy than rapamycin alone. The tFNA/Rapamycin nanocomplex significantly improved bone regeneration in senile osteoporotic mice via synergistic targeting of the cGAS-STING pathway.