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

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.