Modulating intracellular pathways to improve non-viral delivery of RNA therapeutics

• Published in: Advanced drug delivery reviews Vol. 181; p. 114041
• Main Authors: Van de Vyver, Thijs, De Smedt, Stefaan C., Raemdonck, Koen
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.02.2022
• Subjects: Cell Communication - physiology; Cell Membrane - metabolism; Cellular delivery; Cellular uptake; Clustered Regularly Interspaced Short Palindromic Repeats; Conjugates; Drug Evaluation, Preclinical; Endosomal escape; Humans; Intracellular barriers; Intracellular trafficking; MicroRNAs - administration & dosage; Nanoparticle Drug Delivery System; Nanoparticles; Nucleic acid therapeutics; Oligonucleotides - administration & dosage; RNA - administration & dosage; RNA, Messenger - administration & dosage; RNA, Small Interfering - administration & dosage; RNAi Therapeutics; Transfection - methods; Nanoparticles; Conjugates; Cellular uptake; Intracellular barriers; Intracellular trafficking; Nucleic acid therapeutics; Cellular delivery; Endosomal escape
• ISSN: 0169-409X; 1872-8294
• DOI: 10.1016/j.addr.2021.114041

[Display omitted] RNA therapeutics (e.g. siRNA, oligonucleotides, mRNA, etc.) show great potential for the treatment of a myriad of diseases. However, to reach their site of action in the cytosol or nucleus of target cells, multiple intra- and extracellular barriers have to be surmounted. Several non-viral delivery systems, such as nanoparticles and conjugates, have been successfully developed to meet this requirement. Unfortunately, despite these clear advances, state-of-the-art delivery agents still suffer from relatively low intracellular delivery efficiencies. Notably, our current understanding of the intracellular delivery process is largely oversimplified. Gaining mechanistic insight into how RNA formulations are processed by cells will fuel rational design of the next generation of delivery carriers. In addition, identifying which intracellular pathways contribute to productive RNA delivery could provide opportunities to boost the delivery performance of existing nanoformulations. In this review, we discuss both established as well as emerging techniques that can be used to assess the impact of different intracellular barriers on RNA transfection performance. Next, we highlight how several modulators, including small molecules but also genetic perturbation technologies, can boost RNA delivery by intervening at differing stages of the intracellular delivery process, such as cellular uptake, intracellular trafficking, endosomal escape, autophagy and exocytosis.