Inflammatory and immune-mediated toxicity of lipid nanoparticles

Lipid nanoparticles (LNPs) have emerged as promising drug delivery systems. However, side effects such as inflammation, hepatotoxicity, and excessive immune responses remain major challenges. A comprehensive understanding of the mechanisms underlying these adverse effects is crucial to improving the safety of LNP-based therapeutics. Ionizable lipids can activate the NLRP3 (NOD-, LRR-, and pyrin domain-containing protein 3) inflammasome, resulting in cellular damage and the release of pro-inflammatory cytokines. Polyethylene glycol (PEG)-lipids are known to trigger acute hypersensitivity reactions, including anaphylaxis and pseudo-allergies, via the induction of anti-PEG antibodies. In addition, phospholipids and cholesterol may also contribute to toxicity through oxidation or accumulation. To address these issues, a variety of strategies are actively being explored, such as replacing ionizable lipids with biodegradable materials and developing novel surface modification technologies to mitigate anti-PEG immune responses. This review aims to provide an in-depth overview of the mechanisms of toxicity and immune activation induced by the major lipid components of LNPs and to propose strategies for improving toxicity evaluation systems. These efforts are expected to contribute to the development of next-generation LNPs with enhanced safety profiles.