Physiological Barriers and Strategies of Lipid‐Based Nanoparticles for Nucleic Acid Drug Delivery

Abstract

Lipid‐based nanoparticles (LBNPs) are currently the most promising vehicles for nucleic acid drug (NAD) delivery. Although their clinical applications have achieved success, the NAD delivery efficiency and safety are still unsatisfactory, which are, to a large extent, due to the existence of multi‐level physiological barriers in vivo. It is important to elucidate the interactions between these barriers and LBNPs, which will guide more rational design of efficient NAD vehicles with low adverse effects and facilitate broader applications of nucleic acid therapeutics. In this review, we describe the obstacles and challenges of biological barriers to NAD delivery at systemic, organ, sub‐organ, cellular and subcellular levels. We comprehensively review the strategies to overcome these barriers, mainly including physically/chemically engineering LBNPs and directly modifying physiological barriers by auxiliary treatments. We then discuss the potentials and challenges for successful translation of these preclinical studies into the clinic. In the end, we address a forward look at the strategies on manipulating protein corona (PC), which may pull off the trick of overcoming those physiological barriers and significantly improve the efficacy and safety of LBNP‐based NADs delivery.This article is protected by copyright. All rights reserved

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