Abstract

Conventional nanocarriers are readily cleared by macrophages in the liver, with only a minimal fraction reaching hepatocytes. This limitation has been effectively overcome in clinically approved lipid nanoparticles (LNPs) through the incorporation of ionizable lipids. Inspired by this property, we explored whether incorporating ionizable lipids into the lipid bilayer membrane of mesoporous silica nanoparticles (silicasomes) could similarly enhance their hepatic cellular uptake. We developed ionizable silicasomes (I-silicasomes) and systematically compared them with ionizable liposomes (I-liposomes), as well as their conventional counterparts (C-silicasomes and C-liposomes). Surprisingly, the I-silicasomes did not enhance hepatocyte uptake in vitro, whereas I-liposomes exhibited markedly higher internalization efficiency. Although both I-silicasomes and I-liposomes showed substantial liver accumulation in vivo, flow cytometry analysis revealed minimal uptake of I-silicasomes by hepatic parenchymal cells, with no statistical difference from that of C-silicasomes. In contrast, I-liposomes exhibited higher delivery efficiency compared with C-liposomes. SDS-PAGE analysis indicated that all particles except I-liposome exhibited very weak ApoE adsorption. Subsequent nano LC-MS/MS analysis further confirmed the low ApoE adsorption affinity of both C-silicasomes and I-silicasomes after serum incubation, which may account for their limited hepatocyte targeting. Collectively, these findings provide valuable information for guiding the future design and optimization strategies in liver-targeted nanocarrier development.