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

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.