Background The prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) is rapidly increasing with high risk to develop cirrhosis, hepatocellular carcinoma (HCC) and other end-stage liver diseases. However, only two drugs, resmetirom and semaglutide, have been approved by the US food and drug administration (FDA) for the treatment of MASLD, with relative low efficient and obvious side effects. Nanomaterials emerged with constantly growing availability of disease therapy benefiting from their well biocompatibility and appropriate properties. Objective The aim of our present study is to identify and fabricate new nanoparticles with high clinical translational potential for MASLD therapy. Design We systematically screened biocompatible nanoparticles for anti- MASLD capacities in vitro by evaluating their regulatory effects on perilipin-2 (PLIN2), the key molecule in lipid droplet (LD) formation and stability. The exact effects and molecular mechanisms of the identified nanoparticle on MASLD were explored in both cellular and animal models. Results We identified a carboxyl fullerene derivative, named four malonate groups-substituted C 70 fullerene (QF70), as the most potent candidate for MASLD therapy. Notably, QF70 could facilitate lysosomal degradation of PLIN2. More importantly, oral administration of QF70 robustly blocked both diet-induced and leptin deficiency-induced MASLD development with significant improvement in obesity and insulin resistance. We further validated the clinical application potential of QF70 in MASLD-related metabolic disorders in a non-primate model. Conclusions This study provides proof-of-concept supporting a nanoparticle-based agent as a LD homeostasis-targeted therapeutic to treat MASLD and related metabolic diseases.