Prodrug‐Doped ROS‐Responsive Lipid Nanoparticle for Enhanced mRNA Delivery and Synergistic Anti‐Tumor Therapy

Abstract Lipid nanoparticSle (LNP) represents the most advanced mRNA delivery platform for the development of effective cancer therapeutics. Nevertheless, conventional LNP‐mRNA systems are hindered by inadequate endosomal release capability and a lack of synergistic integration with complementary therapeutic approaches. Herein, a reactive oxygen species (ROS)‐responsive prodrug‐doped LNP (LNP‐Pro) that can enhance mRNA delivery efficacy and enable synergistic anti‐tumor therapy is reported. A camptothecin (CPT)‐based prodrug, conjugated to a PEG‐containing block polymer via a ROS‐cleavable linker, is successfully incorporated into clinically approved LNP formulations shown in a report. It shows that LNP‐Pro can respond to the elevated ROS microenvironment in tumor cells, displaying superior delivery capacity in tumor cells relative to normal cells. Furthermore, LNP‐Pro exhibits significantly enhanced mRNA delivery efficacy compared to conventional formulations. In vitro and in vivo studies confirm that LNP‐Pro loaded with therapeutic mRNA synergizes with CPT chemotherapeutic to induce tumor cell apoptosis, achieving significant tumor growth inhibition in a murine model with excellent biocompatibility. Thus, this strategy integrates stimulus‐responsive prodrugs with LNP systems, providing a versatile platform for mRNA‐based cancer therapy.