Scavenger Receptor Class B Type 1 Mediated Transport Enables Delivery Across Capillarized Liver Sinusoids in Metabolic Dysfunction-Associated Steatohepatitis

Abstract Liver fibrosis in metabolic dysfunction associated steatohepatitis (MASH) lacks effective therapies, in part because therapeutic agents poorly penetrate the capillarized sinusoidal endothelium. As fibrosis progresses, liver sinusoidal endothelial cells (LSECs) become defenestrated and restrict trans-sinusoidal exchange, thereby limiting drug access to hepatic stellate cells (HSCs) within the perisinusoidal space. Here, we developed a lipoprotein mimetic liposomal nanocarrier, SV@SRB-Lip, to exploit scavenger receptor class B type 1 (SR-B1)-associated transendothelial transport across capillarized LSECs and enhance downstream delivery toward HSC-associated fibrotic regions. SV@SRB-Lip was engineered as a simvastatin loaded liposomal platform incorporating an ApoA-I-mimetic SRB peptide, an MMP-responsive linker, and a vitamin A modified lipid moiety. SV@SRB-Lip promoted transport across the LSEC monolayer in vitro, and this effect was reduced by SR-B1 silencing, supporting the involvement of SR-B1-associated endothelial transport. In MASH mice, SV@SRB-Lip enhanced hepatic delivery and distributed toward HSC associated fibrotic regions. The MMP-responsive design increased the relative accessibility of vitamin A within the fibrotic microenvironment, supporting downstream HSC associated uptake. As a result, SV@SRB-Lip increased hepatic simvastatin accumulation, suppressed HSC activation and collagen deposition, and improved MASH associated fibrosis. These findings suggest that SR-B1-associated endothelial transport can be harnessed to overcome the capillarized sinusoidal barrier and improve antifibrotic nanomedicine delivery in MASH.