Effect of Lipid Nanoparticle Physico-Chemical Properties and Composition on Their Interaction with the Immune System

Abstract

Lipid nanoparticles (LNPs) have shown promise as a delivery system for nucleic acid-based therapeutics, including DNA, siRNA, and mRNA vaccines. The immune system plays a critical role in the response to these nanocarriers, with innate immune cells initiating an early response and adaptive immune cells mediating a more specific reaction, sometimes leading to potential adverse effects. Recent studies have shown that the innate immune response to LNPs is mediated by Toll-like receptors (TLRs) and other pattern recognition receptors (PRRs), which recognize the lipid components of the nanoparticles. This recognition can trigger the activation of inflammatory pathways and the production of cytokines and chemokines, leading to potential adverse effects such as fever, inflammation, and pain at the injection site. On the other hand, the adaptive immune response to LNPs appears to be primarily directed against the protein encoded by the mRNA cargo, with little evidence of an ongoing adaptive immune response to the components of the LNP itself. Understanding the relationship between LNPs and the immune system is critical for the development of safe and effective nucleic acid-based delivery systems. In fact, targeting the immune system is essential to develop effective vaccines, as well as therapies against cancer or infections. There is a lack of research in the literature that has systematically studied the factors that influence the interaction between LNPs and the immune system and further research is needed to better elucidate the mechanisms underlying the immune response to LNPs. In this review, we discuss LNPs' composition, physico-chemical properties, such as size, shape, and surface charge, and the protein corona formation which can affect the reactivity of the immune system, thus providing a guide for the research on new formulations that could gain a favorable efficacy/safety profile.

Keywords: helper lipids; immune response; ionizable cationic lipids; lipid nanoparticles; physico-chemical properties; protein corona.

Figure 1

Even slight modifications can change the properties of an LNP. (A) By modifying the molar ratio of PEG or the preparation parameters, it is possible to change the LNP size. (B) The surface charge of the LNP can be modified by replacing or adding phospholipids to a charged lipid. (C) Different PEG–lipid conjugates can be obtained, such as modifying the PEG molecular weight, to influence LNP size, zeta potential, and stability. (D) Adjuvants can be added to the formulation to enhance the immune reaction for LNP-based mRNA vaccines. (E) There are several methods for administering LNPs, including intravenous (IV), intramuscular (IM), intradermal (ID), subcutaneous (SC), and intranasal (IN). An appropriate route of administration must be determined based on an understanding of the anatomy of the inoculation site and the induced immune action. Reprinted with permission from [4].

Figure 2

Cryo-TEM image of LNP prepared in the presence of siRNA: LNPs exhibit stacked bilayer structure (left); representative image of LNP structure (right). Reprinted with permission from [21]. Copyright 2018 American Chemical Society.

Figure 3

Schematic illustration of biological properties affected by the LNP physico-chemical properties.

Figure 4

Illustration of LNPs structure and components. Reprinted with permission [24].

Figure 5

Schematic representation of cationic and ionizable lipids and their components (headgroup, linker, and tail). Reprinted with permission from [30]. Copyright 2022 American Chemical Society.

Figure 6

The illustration underscores the primary challenges and drawbacks associated with LNP vaccines. One significant opportunity lies in the ability to modify the protein corona composition, which can help mitigate off-target accumulation and enhance the interaction of LNPs with antigen-presenting cells and dendritic cells. This, in turn, has the potential to significantly improve vaccine efficacy. Reprinted with permission [38].