Ionizable polymeric micelles (IPMs) for efficient siRNA delivery

Lipid nanoparticles (LNPs) are widely used for nucleic acid delivery but face challenges like limited targeting and accelerated blood clearance. We design three ionizable oligo-mers (IOs) that, with PLA-PEG, form Ionizable Polymeric Micelles (IPMs), a potential siRNA delivery system, which can achieve lysosomal escape. FAPi-modified IPMs (FAPi-IPMs) show higher targeting of activated hepatic stellate cells (HSCs) compared to hepatocytes, silencing both HSP47 and HMGB1, reducing collagen secretion and liv-er inflammation, effectively treating fibrosis. Moreover, IPMs and FAPi-IPMs mitigate accelerated blood clearance and produce fewer PEG antibodies than LNPs. Unlike LNPs, which adsorb apolipoprotein E (ApoE), IPMs and FAPi-IPMs show minimal apolipoprotein adsorption, differentiating their targeting effects from LNPs. In conclu-sion, IPMs represent an alternative nucleic acid delivery system with superior targeting and reduced immune clearance.