Decoding Undesirable Inflammatory Responses of Nucleic Acid‐Delivering Lipid Nanoparticles

ABSTRACT Lipid nanoparticles (LNPs) are transformative vectors for nucleic acid delivery, proven safe and effective in COVID‐19 mRNA vaccines, and enabling advances in cancer immunotherapy and gene editing. However, their inherent immunogenicity presents a double‐edged sword: beneficial adjuvant effects in vaccination can become detrimental inflammatory responses in applications like treating inflammatory/fibrotic diseases or gene editing‐based therapies. This review comprehensively evaluates LNP‐associated inflammation and mitigation strategies. We begin with an in‐depth analysis of molecular mechanisms, detailing how specific lipid components, endocytic pathway activation, and nucleic acid sensing drive immune stimulation. Key modulatory factors, including LNP structural characteristics, administration routes, and biodistribution, are examined. We then explore cutting‐edge engineering approaches to circumvent immunogenicity, encompassing structure‐guided design of ionizable lipids, sophisticated biomimetic strategies using natural membrane coatings, innovative co‐delivery systems incorporating anti‐inflammatory agents, and emerging technologies for immune‐evasive LNPs. By elucidating the intricate relationship between nanocarrier physicochemical properties and host immune recognition, while addressing translational hurdles, this review provides critical insights for developing safer, next‐generation LNPs tailored for diverse therapeutic applications.