Exosome‐Inspired Proteolipid Nanoparticles Enable Safe, Extrahepatic RNAi–Chemo Therapy Through Cholesterol‐Free, Tumor‐Preferential Delivery

ABSTRACT

Lipid nanoparticle (LNP)–enabled genetic medicines are reshaping cancer therapy yet remain constrained by liver‐biased tropism, dose‐limiting toxicities, and limited efficacy in refractory solid tumors such as pancreatic ductal adenocarcinoma (PDAC). Here, exosome‐inspired proteolipid nanoparticles (Em‐pLNPs) are developed to embed three exosomal membrane proteins within an ionizable lipid matrix to support safe, extrahepatic delivery of combinatorial gene–chemo payloads. Em‐pLNPs are generated by one‐step microfluidic mixing to incorporate the tetraspanins CD63 and CD81 and the “don't‐eat‐me” marker CD47 into the lipid shell, co‐encapsulate diverse nucleic acid and small‐molecule cargos, and enable modular CD44‐targeted surface functionalization. Following systemic administration in orthotopic PDAC models, Em‐pLNPs exhibit prolonged circulation, preferential extrahepatic tumor accumulation, deep penetration of desmoplastic stroma, and efficient cytosolic delivery, while markedly improving tissue tolerability relative to ligand‐decorated clinical LNP benchmarks. Formulated with an RNAi–chemo cocktail (siKRAS, siIL‐6, and gemcitabine), Em‐pLNPs permit repeated intravenous dosing that drives robust, synergistic tumor regression and mitigates chemoresistance. By coupling exosome‐like immune evasion and tissue tropism with the manufacturability and high gene‐loading capacity of LNPs, Em‐pLNPs define a translational proteolipid platform for safe extrahepatic gene therapy against refractory solid tumors.