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

摘要

Messenger RNA (mRNA) is an emerging class of biotherapeutics for vaccinedevelopment and genome editing. Efficacious delivery and control ofmRNA functionality selectively to disease cells remains the major challengein developing mRNA therapeutics. Herein, reactive oxygen species (ROS)-degradable lipid nanoparticles containing a thioketal (TK) moiety to delivermRNA into cells are reported, selectively releasing mRNA in tumor cells forenhanced gene expression. By screening a library of parallelly synthesizedROS-degradable lipids, it has been identified that BAmP-TK-12 delivers mRNAone-fold more potent in tumor cells than in non-cancerous cells. Furthermore,the delivery of mRNA encoding DUF5, a bacterial-derived RAS protease usingBAmP-TK-12 enables generic depletion of mutant RAS of tumor cells, showinga significantly improved antitumor effect than small molecule-based RASinhibitor. It has been believed that the strategy of tumor cell-selective mRNAdelivery using ROS-degradable lipid nanoparticles can be expanded to thebroad range of bacterial effectors for rewiring cancer cell signaling and developingadvanced biotherapeutics.