Targeted inhibition of inflammatory liver macrophages with a multifunctional nanoparticle ameliorates metabolic dysfunction–associated steatohepatitis

Despite metabolic dysfunction–associated steatohepatitis (MASH) being a significant global health concern, there are few effective ways to prevent or treat MASH. Evidence from preclinical and clinical studies suggests that inflammatory polarization of Kupffer cells (KCs) and infiltration of monocyte-derived macrophages (MDMs) in liver macrophages play an essential role in the initiation and progression of MASH. Herein, we reported a liposomal nanoparticle (NP-OMg) that targets suppressive oligodeoxynucleotide (sODN) and magnesium ions (Mg 2+ ) to KCs and MDMs. sODN acted as a potent inhibitor of multiple pattern recognition receptors (PRRs), while Mg 2+ was chosen for its anti-oxidative and anti-pyroptotic effects, and its capability of coordinating with sODN in NP-OMg. Intravenously administrated NP-OMg was primarily engulfed by both KCs and MDMs in mouse liver. Therapeutically, NP-OMg mitigated hepatic steatosis, inflammation and fibrosis, and restored liver functions in mouse models of metabolic dysfunction–associated steatotic liver disease (MASLD)/MASH. Mechanistically, RNA-sequencing analysis revealed that NP-OMg largely reversed the aberrant gene expression and signaling pathways involved in the pathogenesis of MASLD/MASH. Through comprehensive targeting of inflammatory pathways in liver macrophages, NP-OMg treatment significantly reduced production of inflammatory cytokines/chemokines and decreased the liver recruitment of Ly6c high inflammatory MDMs. These findings demonstrate the potential of a new liver macrophage-targeted nanomedicine strategy for the treatment of MASH.