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

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.