The immunostimulatory nature of mRNA lipid nanoparticles

Preeti Sharma, Daniek Hoorn, Anjaiah Aitha, Dor Breier, Dan Peer

Research output: Contribution to journalReview articlepeer-review

7 Scopus citations


mRNA-Lipid nanoparticles (LNPs) are at the forefront of global medical research. With the development of mRNA-LNP vaccines to combat the COVID-19 pandemic, the clinical potential of this platform was unleashed. Upon administering 16 billion doses that protected billions of people, it became clear that a fraction of them witnessed mild and in some cases even severe adverse effects. Therefore, it is paramount to define the safety along with the therapeutic efficacy of the mRNA-LNP platform for the successful translation of new genetic medicines based on this technology. While mRNA was the effector molecule of this platform, the ionizable lipid component of the LNPs played an indispensable role in its success. However, both of these components possess the ability to induce undesired immunostimulation, which is an area that needs to be addressed systematically. The immune cell agitation caused by this platform is a two-edged sword as it may prove beneficial for vaccination but detrimental to other applications. Therefore, a key challenge in advancing the mRNA-LNP drug delivery platform from bench to bedside is understanding the immunostimulatory behavior of these components. Herein, we provide a detailed overview of the structural modifications and immunogenicity of synthetic mRNA. We discuss the effect of ionizable lipid structure on LNP functionality and offer a mechanistic overview of the ability of LNPs to elicit an immune response. Finally, we shed some light on the current status of this technology in clinical trials and discuss a few challenges to be addressed to advance the field.

Original languageEnglish
Article number115175
JournalAdvanced Drug Delivery Reviews
StatePublished - Feb 2024
Externally publishedYes

Bibliographical note

Publisher Copyright:
© 2024 Elsevier B.V.


Cholesterol is often incorporated in the LNPs to enhance stability and regulate membrane fluidity. Since cholesterol occurs naturally in cell membranes, incorporating cholesterol improves the biocompatibility of LNPs and promotes endocytosis. On the other hand, PEG imparts stealth properties to the LNPs, making them less prone to recognition and clearance by the immune system. This, in turn, allows the LNPs to circulate in the bloodstream longer. Phospholipids such as 1,2-Distearoyl-sn-glycero-3-phosphocholine (DSPC) are used as structural lipids as they spontaneously organize into lipid bilayers. Additionally, their high phase transition temperatures confer membrane stability to the LNP.[101] We direct the reader to refer to other review articles for details on the helper lipids.

FundersFunder number


    • Adverse events
    • Immunogenicity
    • Ionizable lipids
    • Structure–activity relationship
    • mRNA vaccines


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