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.