Kaitlin Mrksich , Marshall S. Padilla , Michael J. Mitchell
{"title":"Breaking the final barrier: Evolution of cationic and ionizable lipid structure in lipid nanoparticles to escape the endosome","authors":"Kaitlin Mrksich , Marshall S. Padilla , Michael J. Mitchell","doi":"10.1016/j.addr.2024.115446","DOIUrl":null,"url":null,"abstract":"<div><div>In the past decade, nucleic acid therapies have seen a boon in development and clinical translation largely due to advances in nanotechnology that have enabled their safe and targeted delivery. Nanoparticles can protect nucleic acids from degradation by serum enzymes and can facilitate entry into cells. Still, achieving endosomal escape to allow nucleic acids to enter the cytoplasm has remained a significant barrier, where less than 5% of nanoparticles within the <em>endo</em>-lysosomal pathway are able to transfer their cargo to the cytosol. Lipid-based drug delivery vehicles, particularly lipid nanoparticles (LNPs), have been optimized to achieve potent endosomal escape, and thus have been the vector of choice in the clinic as demonstrated by their utilization in the COVID-19 mRNA vaccines. The success of LNPs is in large part due to the rational design of lipids that can specifically overcome endosomal barriers. In this review, we chart the evolution of lipid structure from cationic lipids to ionizable lipids, focusing on structure–function relationships, with a focus on how they relate to endosomal escape. Additionally, we examine recent advancements in ionizable lipid structure as well as discuss the future of lipid design.</div></div>","PeriodicalId":7254,"journal":{"name":"Advanced drug delivery reviews","volume":"214 ","pages":"Article 115446"},"PeriodicalIF":15.2000,"publicationDate":"2024-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Advanced drug delivery reviews","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0169409X24002680","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"PHARMACOLOGY & PHARMACY","Score":null,"Total":0}
引用次数: 0
Abstract
In the past decade, nucleic acid therapies have seen a boon in development and clinical translation largely due to advances in nanotechnology that have enabled their safe and targeted delivery. Nanoparticles can protect nucleic acids from degradation by serum enzymes and can facilitate entry into cells. Still, achieving endosomal escape to allow nucleic acids to enter the cytoplasm has remained a significant barrier, where less than 5% of nanoparticles within the endo-lysosomal pathway are able to transfer their cargo to the cytosol. Lipid-based drug delivery vehicles, particularly lipid nanoparticles (LNPs), have been optimized to achieve potent endosomal escape, and thus have been the vector of choice in the clinic as demonstrated by their utilization in the COVID-19 mRNA vaccines. The success of LNPs is in large part due to the rational design of lipids that can specifically overcome endosomal barriers. In this review, we chart the evolution of lipid structure from cationic lipids to ionizable lipids, focusing on structure–function relationships, with a focus on how they relate to endosomal escape. Additionally, we examine recent advancements in ionizable lipid structure as well as discuss the future of lipid design.
期刊介绍:
The aim of the Journal is to provide a forum for the critical analysis of advanced drug and gene delivery systems and their applications in human and veterinary medicine. The Journal has a broad scope, covering the key issues for effective drug and gene delivery, from administration to site-specific delivery.
In general, the Journal publishes review articles in a Theme Issue format. Each Theme Issue provides a comprehensive and critical examination of current and emerging research on the design and development of advanced drug and gene delivery systems and their application to experimental and clinical therapeutics. The goal is to illustrate the pivotal role of a multidisciplinary approach to modern drug delivery, encompassing the application of sound biological and physicochemical principles to the engineering of drug delivery systems to meet the therapeutic need at hand. Importantly the Editorial Team of ADDR asks that the authors effectively window the extensive volume of literature, pick the important contributions and explain their importance, produce a forward looking identification of the challenges facing the field and produce a Conclusions section with expert recommendations to address the issues.