Endosomal escape: A bottleneck for LNP- mediated therapeutics

• 成果类型: Article
• 署名作者: Chatterjee, Sushmita; Kon, Edo; Sharma, Preeti; Peer, Dan
• 署名单位: Tel Aviv University; Tel Aviv University; Tel Aviv University; Tel Aviv University
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-10710
• DOI: 10.1073/pnas.2307800120
• 发表日期: 2024-03-12
• 关键词: calcium-phosphate nanoparticles; cell-penetrating peptides; messenger-rna vaccines; fusogenic liposomes; lipid nanoparticles; sirna delivery; proton sponge; intracellular delivery; systemic delivery; TRAFFICKING

摘要

Lipid nanoparticles (LNPs) have recently emerged as a powerful and versatile clinically approved platform for nucleic acid delivery, specifically for mRNA vaccines. A major bottleneck in the field is the release of mRNALNPs from the endosomal pathways into the cytosol of cells where they can execute their encoded functions. The data regarding the mechanism of these endosomal escape processes are limited and contradicting. Despite extensive research, there is no consensus regarding the compartment of escape, the cause of the inefficient escape and are currently lacking a robust method to detect the escape. Here, we review the currently known mechanisms of endosomal escape and the available methods to study this process. We critically discuss the limitations and challenges of these methods and the possibilities to overcome these challenges. We propose that the development of currently lacking robust, quantitative high- throughput techniques to study endosomal escape is timely and essential. A better understanding of this process will enable better RNA- LNP designs with improved efficiency to unlock new therapeutic modalities.