A Combinatorial Library of Biodegradable Lipid Nanoparticles Preferentially Deliver mRNA into Tumor Cells to Block Mutant RAS Signaling

Abstract Messenger RNA (mRNA) is an emerging class of biotherapeutics for vaccine development and genome editing. Efficacious delivery and control of mRNA functionality selectively to disease cells remains the major challenge in developing mRNA therapeutics. Herein, reactive oxygen species (ROS)‐degradable lipid nanoparticles containing a thioketal (TK) moiety to deliver mRNA into cells are reported, selectively releasing mRNA in tumor cells for enhanced gene expression. By screening a library of parallelly synthesized ROS‐degradable lipids, it has been identified that BAmP‐TK‐12 delivers mRNA one‐fold more potent in tumor cells than in non‐cancerous cells. Furthermore, the delivery of mRNA encoding DUF5, a bacterial‐derived RAS protease using BAmP‐TK‐12 enables generic depletion of mutant RAS of tumor cells, showing a significantly improved antitumor effect than small molecule‐based RAS inhibitor. It has been believed that the strategy of tumor cell‐selective mRNA delivery using ROS‐degradable lipid nanoparticles can be expanded to the broad range of bacterial effectors for rewiring cancer cell signaling and developing advanced biotherapeutics.