A multifunctional lipid-lowering nanotherapeutic alleviates lipid deposition associated microglial dysfunction

AIM: Microglial lipid deposition is increasingly recognized as a critical feature of disturbed lipid homeostasis, and lipid droplet driven pathological cascades can reinforce oxidative and mitochondrial stress, creating a vicious cycle that accelerates microglial dysfunction. Reducing lipid droplet burden is therefore be a useful strategy for alleviating microglial dysfunction. MATERIALS AND METHODS: Uniform mesoporous polydopamine (MPDA) nanoparticles loaded with berberine (BBR) were engineered to construct the nanotherapeutic drug PB. Based on evaluation of free radical scavenging and lipid adsorption properties, therapeutic performance was examined by quantifying lipid droplet content, triglyceride levels, ROS levels, mitochondrial membrane potential, ATP production, and inflammatory factor TNF-α secretion in an oleic acid induced lipid overload BV2 cell model. RESULTS: MPDA exhibited high lipid binding capacity and strong antioxidant activity. BBR loading exerted a synergistic effect to mitigate lipid droplet accumulation, intracellular and mitochondrial ROS burst, and mitochondrial oxidative damage, and ultimately reducing the production of inflammatory factor TNF-α in lipid challenged BV2 cells. CONCLUSION: PB integrates mesoporous lipid adsorption, intrinsic redox buffering, and berberine loading, thereby attenuating oxidative stress and mitochondrial injury associated with lipid overload in microglia. This work highlights the potential of lipid-lowering nanotherapeutic strategies for intervening in lipid-overload-associated microglial dysfunction.