Macrophage-Targeted Fullerene Potentiates Redox Homeostasis Regulation and Reprograms Macrophage Polarization to Ameliorate Hepatic Steatosis

Hepatic steatosis, the initial stage of metabolic disorder-associated fatty liver disease (MAFLD), affects an approximately 25% population worldwide. Macrophages play a central pathological role by coordinating aberrant redox homeostasis, persistent inflammation, and insulin resistance, thereby driving disease progression. Scavenging excess reactive oxygen species (ROS) to inhibit macrophage polarization and inflammatory cascades represents a promising therapeutic strategy. Leveraging the intrinsic ROS-scavenging capability of fullerene, we fabricated bis-carboxylated fullerene amidated with mannose (BCFM) for the macrophage-targeted therapy of hepatic steatosis. BCFM preferentially binds to mannose receptors overexpressed on macrophages, enabling efficient cellular internalization. Consequently, BCFM rapidly alleviated oxidative stress, inhibited M1-type macrophage polarization, and reduced the level of inflammation. Furthermore, BCFM treatment effectively ameliorated the hepatic pro-inflammatory microenvironment and mitigated hepatic steatosis in ob/ob mice. Collectively, this study presents an alternative therapeutic approach for hepatic steatosis through the active modulation of redox homeostasis and the reprogramming of inflammatory macrophage polarization.