Cholesterol-driven mitochondrial rejuvenation by quercetin nanotherapeutics restores implant osseointegration in diabetes

Poorly controlled diabetes significantly compromises implant osseointegration, with mitochondrial dysfunction in bone marrow mesenchymal stem cells (BMSCs) emerging as a key pathological regulator. However, effective targeted therapies to achieve mitochondrial rejuvenation are still lacking. Given this, we specifically fabricated Qe@TNS coatings, a nanostructured platform that enables localized quercetin (Qe) delivery. Mechanistically, hyperglycemia-induced oxidative damage disrupts cholesterol metabolism in BMSCs, initiating a pathological transition of lipid rafts (LR) from functional liquid-ordered (Lo) to dysfunctional liquid-disordered (Ld) phases (the “switch-off” state). This impairs the LR-dependent mitochondrial quality control (MQC) networks, leading to the loss of mitochondrial homeostasis. Remarkably, Qe@TNS reversed this process through an “off-to-on” switching mechanism, where released Qe restored cholesterol influx, promoting LR conformational transition to the Lo phase, and activating the antioxidant unit of LR-scavenger receptor class B type I (SR-B1) to mitigate oxidative damage in BMSCs. Meanwhile, hyperglycemia promotes the abnormal accumulation of succinate in mitochondria, triggering the succinate/HIF-1α/IL-1β pro-inflammatory axis. Qe@TNS was found to inhibit this signaling cascade while upregulating IL-10 expression. By coordinately addressing oxidative stress and inflammation, Qe@TNS effectively rejuvenated mitochondrial functions and enhanced osteogenic capacity, establishing a novel nanotherapeutic strategy for restoring implant osseointegration in diabetes. • Qe@TNS restores impaired osseointegration by reversing mitochondrial dysfunction through localized quercetin delivery. • Quercetin enhances cholesterol influx and thereby activating the LR-(SR-B1) antioxidant complex to mitigate oxidative stress. • Qe@TNS suppresses the succinate/HIF-1α/IL-1β axis and enhances IL-10 expression, alleviating pro-inflammatory responses. • An “off-to-on” cholesterol-mediated switch underlies Qe@TNS-induced mitochondrial rejuvenation and osteogenesis in hyperglycemia.