PEG-free Lipid Nanoparticles for mRNA Delivery: Superhydrophilic Sulfoxide Polymer Coatings
Lipid nanoparticles (LNPs) are the most widely applied nanocarriers for mRNA delivery in clinical use. However, the limited stability and increasingly recognized immunogenicity of PEG-based LNP formulations are potential impediments to the more widespread development of mRNA therapeutics. To address shortcomings in current LNP polymer coatings, we have developed a polymer-lipid conjugate based on the low-fouling sulfoxide polymer poly(2-(methylsulfinyl)ethyl acrylate) (PMSEA). The results show that LNPs formed from the PMSEA-DSPE conjugates with optimized polymer chain length have excellent stability, highly effective shielding, and low immunogenicity, favorable properties for PMSEA-DSPE to be incorporated as a component of mRNA nanocarriers. mRNA-LNP formulations were prepared with PMSEA-DSPE as an alternative to the PEGylated formulations. The stability, <i>in vitro</i> behavior, and transfection efficiency of the mRNA nanocarriers were evaluated, with PMSEA providing superior transfection efficiency compared with the PEG equivalents. This work demonstrates the potential of PMSEA mRNA-LNPs for further development as therapeutic delivery vehicles.
Authors
- Andrew K. Whittaker (ORCID: https://orcid.org/0000-0002-1948-8355)
- Changkui Fu (ORCID: https://orcid.org/0000-0002-2444-607X)
- On Ting Choy (ORCID: https://orcid.org/0000-0002-1932-7797)
- Nicholas L. Fletcher (ORCID: https://orcid.org/0000-0002-2993-833X)
- Stephen John Kent (ORCID: https://orcid.org/0000-0002-8539-4891)
- Gayathri R. Ediriweera (ORCID: https://orcid.org/0000-0002-8782-8745)
- Mai N. Vu (ORCID: https://orcid.org/0000-0001-5570-8557)
- Chunying Chen (ORCID: https://orcid.org/0000-0002-6027-0315)
- James Humphries (ORCID: https://orcid.org/0000-0002-2603-6947)
- Mingdi Hu (ORCID: https://orcid.org/0000-0002-5568-5321)
- Rong Cai (ORCID: https://orcid.org/0009-0007-7765-3877)
Institutions
- Academy of Medical Sciences (GB)
- Australian Research Council (AU)
- Queensland University of Technology (AU)
- The University of Queensland (AU)
- The University of Melbourne (AU)
- Chinese Academy of Sciences (CN)
- Chinese Academy of Medical Sciences & Peking Union Medical College (CN)
- Australian Regenerative Medicine Institute (AU)
- Center for NanoScience (DE)
- Melbourne Sexual Health Centre (AU)
- Peter Doherty Institute (AU)
- Institute of Bioengineering and Nanotechnology (SG)
- National Center for Nanoscience and Technology (CN)
- ARC Centre of Excellence in Advanced Molecular Imaging (AU)
- ARC Centre of Excellence for Plant Success in Nature and Agriculture (AU)
- Monash University (AU)
- Center for Excellence in Education (US)
Publication Details
- Journal
- Biomacromolecules
- Published
- 2025-11-27
- DOI
- https://doi.org/10.1021/acs.biomac.5c01899
- Citations
- 2
- Primary Topic
- RNA Interference and Gene Delivery
- Type
- article
- Field-Weighted Citation Impact
- 1.61