Replacing poly(ethylene glycol) with RAFT lipopolymers in mRNA lipid nanoparticle systems for effective gene delivery.

Autor: Hassanel DNBP; Monash Institute of Pharmaceutical Sciences, Monash University, 399 Royal Parade, Parkville, VIC 3052, Australia., Pilkington EH; Monash Institute of Pharmaceutical Sciences, Monash University, 399 Royal Parade, Parkville, VIC 3052, Australia; Peter Doherty Institute for Infection and Immunity, University of Melbourne, 792 Elizabeth St, Melbourne, VIC 3000, Australia., Ju Y; Peter Doherty Institute for Infection and Immunity, University of Melbourne, 792 Elizabeth St, Melbourne, VIC 3000, Australia; School of Science and School of Health and Biomedical Sciences, RMIT University, 264 Plenty Rd, Mill Park, VIC 3083, Australia., Kent SJ; Peter Doherty Institute for Infection and Immunity, University of Melbourne, 792 Elizabeth St, Melbourne, VIC 3000, Australia., Pouton CW; Monash Institute of Pharmaceutical Sciences, Monash University, 399 Royal Parade, Parkville, VIC 3052, Australia., Truong NP; Monash Institute of Pharmaceutical Sciences, Monash University, 399 Royal Parade, Parkville, VIC 3052, Australia. Electronic address: Nghia.Truong@monash.edu.
Jazyk: angličtina
Zdroj: International journal of pharmaceutics [Int J Pharm] 2024 Nov 15; Vol. 665, pp. 124695. Date of Electronic Publication: 2024 Sep 15.
DOI: 10.1016/j.ijpharm.2024.124695
Abstrakt: Lipid nanoparticles (LNPs) have emerged as promising carriers to efficiently transport mRNA into cells for protein translation, as seen with the mRNA vaccines used against COVID-19. However, they contain a widely used polymer - poly(ethylene glycol) (PEG) - which lacks the functionality to be easily modified (which could effectively control the physicochemical properties of the LNPs such as its charge), and is also known to be immunogenic. Thus, it is desirable to explore alternative polymers which can replace the PEG component in mRNA LNP vaccines and therapeutics, while still maintaining their efficacy. Herein, we employed reversible addition-fragmentation chain transfer (RAFT) polymerisation to synthesise five PEG-lipid alternatives that could stabilise LNPs encapsulating mRNA or pDNA molecules. Importantly, the resultant RAFT lipopolymer LNPs exhibit analogous or higher in vivo gene expression and antigen-specific antibody production compared to traditional PEG-based formulations. Our synthesis strategy which allows the introduction of positive charges along the lipopolymer backbone also significantly improved the in vivo gene expression. This work expands the potential of RAFT polymer-conjugated LNPs as promising mRNA carriers and offers an innovative strategy for the development of PEG-free mRNA vaccines and therapeutics.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
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