A Combinatorial Library of Biodegradable Lipid Nanoparticles Preferentially Deliver mRNA into Tumor Cells to Block Mutant RAS Signaling. (10th August 2022)

• Record Type: Journal Article
• Authors: Cai, Weiqi; Luo, Tianli; Chen, Xianghan; Mao, Lanqun; Wang, Ming
• Is Part Of: Advanced functional materials. Volume 32:Number 41(2022)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2022-08-10
• Subjects: lipid nanoparticles -- mRNA deliveries -- RAS inhibition -- ROS‐degradable; Materials -- Periodicals; Chemical vapor deposition -- Periodicals; 620.11
• DOI: 10.1002/adfm.202204947
• Languages: English
• ISSNs: 1616-301X

Abstract

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. Abstract : A novel type of ROS‐degradable lipid nanoparticles is designed to preferentially deliver mRNA into cancer cells. The integration of thioketal moiety into lipids promotes intracellular mRNA release for enhancing protein expression efficiency in tumor cells. An optimal lipid nanoparticle formulation, BAmP‐TK‐12 delivers bacterial effector, DUF5 to deplete mutant RAS of tumor cells, showing a significantly improved antitumor effect than small molecule‐based RAS inhibitor, AMG510.