Lipid Nanoparticles (LNPs) for Therapeutics and Vaccines

The era of COVID-19 has brought to the forefront mRNA-based vaccines.  With the EUA approval of Pfizer and Moderna’s vaccines, the technology which goes into the discovery and manufacturing of this novel class of vaccines has been of public interest.  A complex drug product, mRNA vaccines and therapeutics are unstable and very susceptible to cellular environmental impacts.  A large number of resources have been directed to the effective delivery of the active compound.

At present, lipid nanoparticles (LNPs) are among the most common vectors for in vivo RNA delivery.  Historically, the majority of research involving LNPs was targeted at the treatment of genetic conditions in a variety of tissues, a considerable amount has also been aimed at those which target the immune system. In general, LNPs a composed of a lipid bilayer shell surrounding an aqueous core.  The bilayer shell is created using a combination of different lipids; however, other structures have been reported. The majority of LNP formulations utilize cationic lipids to aid in the complexation of negatively charged RNA, although some anionic and neutral formulations have also been utilized historically. Several studies have indicated that cationic lipids which bear a permanent positive charge have a higher toxicity while being less efficient, significant research into the potency of LNPs has led to the development of new, ionizable lipids and lipid-like materials. Under physiological pH conditions, such lipids and lipidoids are comprised of amine groups that maintain a neutral or mildly cationic surface charge, which are able to reduce nonspecific lipid–protein interactions.  This also facilitates oligonucleotide release in the cytosol. In the endosome, it is suggested that the amine groups are ionized upon acidification aiding in the induction of hexagonal phase structures, thus disrupting the late endosomes membranes, which, in turn, enables cellular uptake and endosomal escape of mRNA into the cytoplasm1.

Many of the components utilized by LNPs to deliver mRNA have also been selected to deliver siRNA, with several clinical studies, having been performed in recent years, delivering siRNA in LNP carries2.  Though the exact formulations used to deliver the much larger mRNA molecules will likely vary from the ones used for siRNA, many of the strategic challenges are the same3.


  1. Reichmuth, A. M., Oberli, M. A., Jaklenec, A., Langer, R., & Blankschtein, D. (2016). mRNA vaccine delivery using lipid nanoparticles. Therapeutic delivery, 7(5), 319–334.
  2. Xue HY, Guo P, Wen W-C, Wong HL. Lipid-based nanocarriers for RNA delivery. Pharm. Des. 2015;21(22):3140–3147.
  3. Kauffman KJ, Dorkin JR, Yang JH, et al. Optimization of lipid nanoparticle formulations for mRNA delivery in vivo with fractional factorial and definitive screening designs. Nano Lett. 2015;15(11):7300–7306.

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