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

Abstract

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.