Fabricating a hepatocyte-targeted fullerene derivative as a new lipid droplet regulator

Abstract Lipid droplets (LDs) are crucial organelles in organisms and hold a critical function in modulating intracellular lipid metabolism and bioenergetic regulation. The homeostasis of LDs directly participates in the onset and progression of non-alcoholic steatohepatitis (NASH) and other metabolic disorders. However, no pharmacological approaches have been developed to target LDs-related dysfunction for metabolic diseases. Here, we systemically screened biocompatible nanoparticles for anti-LDs formation capacities, and identified a carboxyl fullerene derivative, named four malonate groups-substituted C70 fullerene (QF70), as the most potent lead. Notably, QF70 could be directly internalized into hepatocytes and facilitate lysosomal degradation of perilipin-2 (PLIN2), the key molecule in LDs formation and stability. More importantly, oral administration of QF70 robustly blocked both diet- and Leptin deficiency-induced NASH development with significant improvement in obesity and insulin resistance. We further validated the clinical application potential of QF70 in NASH related metabolic disorders in a non-primate model. To our knowledge, this is the first-in-class demonstration for a nanoparticle based agent as a LDs homeostasis-targeted therapeutic to treat metabolic diseases.