Precision targeting of METTL3 via bone-homing bisphosphonate-modified PLGA nanoparticles mitigates osteoporotic bone loss through m6A-PPARα crosstalk in ferroptotic regulation.

Osteoporosis (OP), characterized by progressive bone loss, is closely linked to ferroptosis-induced senescence of bone marrow mesenchymal stem cells (BMSCs). N6-methyladenosine (m6A) modification of peroxisome proliferator-activated receptor alpha (PPARα) mediated by METTL3 has been identified as a crucial regulatory mechanism, although effective targeted interventions remain limited. We engineered bone-homing bisphosphonate-modified poly(lactic-co-glycolic acid) nanoparticles (BP-PLGA) nanoparticles (NPs) to deliver the METTL3 inhibitor (STM2457). The NPs were characterized for size, zeta potential, and drug loading. In vitro, the impact of METTL3 inhibition on ferroptosis and osteogenic differentiation of aged BMSCs was analyzed using flow cytometry, western blotting, and qRT-PCR. In vivo, osteoporotic mouse models were established, and the therapeutic efficacy of nanoparticles-mediated METTL3 inhibition was assessed by micro-CT, histological analysis, and molecular assays. The bone-homing BP-PLGA NPs showed high efficiency in targeting aged BMSCs and sustained release of STM2457. In vitro, METTL3 inhibition reversed m6A hypermethylation of PPARα mRNA, restored PPARα expression, and attenuated ferroptosis in aged BMSCs, promoting osteogenic differentiation. In vivo, nanoparticles treatment significantly increased bone mass density, alleviated osteoporotic bone degeneration, reduced marrow adiposity, and inhibited ferroptosis-related markers in osteoporotic mice. Mechanistically, METTL3 - PPARα crosstalk regulated lipid peroxidation and YAP/TAZ signaling in ferroptotic BMSCs. Our study demonstrates that precision targeting of METTL3 via bone-homing BP-PLGA NPs mitigate osteoporotic bone loss through the m6A-PPARα axis in ferroptotic regulation, providing a promising nanotherapeutic strategy for OP treatment.