Lipid nanoparticle-mediated RNA delivery for immune cell modulation

Abstract

Lipid nanoparticles (LNPs) have emerged as the preeminent nonviral drug delivery vehicles for nucleic acid therapeutics, as exemplified by their usage in the mRNA COVID-19 vaccines. As a safe and highly modular delivery platform, LNPs are attractive for a wide range of applications. In addition to vaccines, LNPs are being utilized as platforms for other immunoengineering efforts, especially as cancer immunotherapies by modulating immune cells and their functionality via nucleic acid delivery. In this review, we focus on the methods and applications of LNP-based immunotherapy in five cell types: T cells, NK cells, macrophages, stem cells, and dendritic cells. Each of these cell types has wide-reaching applications in immunotherapy but comes with unique challenges and delivery barriers. By combining knowledge of immunology and nanotechnology, LNPs can be developed for improved immune cell targeting and transfection, ultimately working toward novel clinical therapeutics.

Keywords: Dendritic cells; Lipid nanoparticles; Macrophages; NK cells; T cells.

Figure 1

Overview of mRNA lipid nanoparticle (LNP) formulation. Excipients of LNPs include an ionizable lipid, a lipid‐anchored PEG, a helper lipid, and a steroid that is mixed with a nucleic acid of interest. The lipid phase and the nucleic acid phase are mixed, often through microfluidics or pipette mixing, to formulate the LNP. The LNP can then be administered in vivo, in vitro to transfect a cell line, or ex vivo, where cells are transfected apart from the body and then readministered. Created with BioRender.

Figure 2

Schematic of lipid nanoparticle (LNP) applications for T cells, NK cells, macrophages, stem cells, and dendritic cells. The LNPs can be encapsulated with a variety of functional cargo including gene editing materials and antigens (left). Depending on the application, the LNP‐based nucleic acid therapy can activate immune cells, facilitate differentiation, repolarize, and install targeting moieties (middle). List of specific applications involving modulating immune cells with LNPs (right) [35, 36, 37, 38, 39]. Created with BioRender.

Figure 3

Schematic representation of the different nanoparticles used to modify NK‐92 and primary NK cells and their limitations and desired effects. Created with BioRender.

Figure 4

Differentiation of totipotent stem cells into endoderm, mesoderm, or ectoderm cells. Created with BioRender.