4.5 Article

Optimization of phospholipid chemistry for improved lipid nanoparticle (LNP) delivery of messenger RNA (mRNA)

Journal

BIOMATERIALS SCIENCE
Volume 10, Issue 2, Pages 549-559

Publisher

ROYAL SOC CHEMISTRY
DOI: 10.1039/d1bm01454d

Keywords

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Funding

  1. National Institutes of Health (NIH) National Institute of Biomedical Imaging and Bioengineering (NIBIB) [R01 EB025192-01A1]
  2. Cystic Fibrosis Foundation (CFF) [SIEGWA18XX0]
  3. Cancer Prevention and Research Institute of Texas (CPRIT) [RP190251]
  4. American Cancer Society (ACS) [RSG-17-01201]
  5. Welch Foundation [I-1855]
  6. National Cancer Institute [5P30CA142543]
  7. Moody Foundation Flow Cytometry Facility
  8. National Science Foundation Graduate Research Fellowship Program (NSF GRFP) [2018270395]

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Research has shown that manipulating the identity of the phospholipid in LNPs can enhance mRNA delivery efficacy, improve endosomal escape, and alter the organ tropism of LNPs. The choice of phospholipid is crucial for designing and optimizing LNPs for improved mRNA delivery and more effective therapeutics.
Lipid nanoparticles (LNPs) have been established as an essential platform for nucleic acid delivery. Efforts have led to the development of vaccines that protect against SARS-CoV-2 infection using LNPs to deliver messenger RNA (mRNA) coding for the viral spike protein. Out of the four essential components that comprise LNPs, phospholipids represent an underappreciated opportunity for fundamental and translational study. We investigated this avenue by systematically modulating the identity of the phospholipid in LNPs with the goal of identifying specific moieties that directly enhance or hinder delivery efficacy. Results indicate that phospholipid chemistry can enhance mRNA delivery by increasing membrane fusion and enhancing endosomal escape. Phospholipids containing phosphoethanolamine (PE) head groups likely increase endosomal escape due to their fusogenic properties. Additionally, it was found that zwitterionic phospholipids mainly aided liver delivery, whereas negatively charged phospholipids changed the tropism of the LNPs from liver to spleen. These results demonstrate that the choice of phospholipid plays a role intracellularly by enhancing endosomal escape, while also driving organ tropism in vivo. These findings were then applied to Selective Organ Targeting (SORT) LNPs to manipulate and control spleen-specific delivery. Overall, selection of the phospholipid in LNPs provides an important handle to design and optimize LNPs for improved mRNA delivery and more effective therapeutics.

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