Targeted Delivery of Bezafibrate via Silica Nanoparticles Restores Mitochondrial Function and Reduces Oxidative Stress in Insulin-Resistant Cells.

Mitochondrial dysfunction and oxidative stress are pivotal drivers of obesity-induced insulin resistance, posing significant challenges to therapeutic efficacy. Bezafibrate, a pan-peroxisome proliferator-activated receptor (PPAR) agonist, enhances mitochondrial metabolism and antioxidant defenses; however, its efficacy is hindered by poor solubility and bioavailability. In this study, we engineered biodegradable periodic mesoporous organosilica (BPMO) nanoparticles to improve bezafibrate delivery and intracellular efficacy. Spectroscopic, circular dichroism, and molecular modeling analyses confirmed that bezafibrate stably binds antioxidant enzymes catalase and superoxide dismutase (SOD), with minimal perturbation to their conformation. Molecular docking and dynamics simulations supported these findings by demonstrating stable binding and increased protein structural integrity. In insulin-resistant human adipose-derived cells (HPAd), BPMO-bezafibrate notably restored mitochondrial membrane potential, enhanced fatty acid oxidation, reduced intracellular reactive oxygen species (ROS), and upregulated endogenous gene expression of PPARγ and adiponectin. Compared to liposomal and free-drug delivery, BPMO-bezafibrate showed higher cellular uptake, reduced cytotoxicity, and improved metabolic rescue. Moreover, in vivo uptake and safety were validated using medaka embryos. Collectively, our findings establish BPMO-assisted bezafibrate delivery as a safe and potent strategy to restore mitochondrial function and redox balance in insulin-resistant cells, offering translational promise for treating metabolic disorders.