脂质纳米颗粒（LNP）作为一种高效的非病毒基因递送载体，在自身免疫性疾病、代谢性疾病及遗传性疾病等的治疗中展现出重要应用潜力。当前临床获批的LNP制剂通常由可电离脂质、磷脂、胆固醇及聚乙二醇（PEG）脂质4种组分构成。然而，上述组分及LNP的体内生物学行为易诱发宿主免疫应答，严重制约了药物的安全性与重复给药疗效，是临床转化应用的关键障碍。深入剖析LNP递送系统引发机体炎症反应的内在机制，系统阐述可电离脂质分子结构优化、PEG脂质替代、LNP表面功能化修饰等多维度非炎症型LNP构建策略。在此基础上，进一步梳理非炎症型LNP在蛋白质替代疗法、基因编辑、预防性疫苗及肿瘤免疫治疗等领域的研究进展，以期为安全、高效的非炎症型LNP递送系统的设计与应用提供理论参考。

Lipid nanoparticles (LNP), as efficient non-viral gene delivery vectors, demonstrate significant application potential in the treatment of autoimmune diseases, metabolic diseases, and genetic disorders. Currently approved LNP formulations typically consist of four components: ionizable lipids, phospholipids, cholesterol, and PEG-lipids. However, these components and the in vivo biological behavior of LNP tend to induce host immune responses, severely compromising drug safety and the efficacy of repeated dosing, thereby posing a critical barrier to clinical translation. This review delves into the mechanisms underlying LNP-induced inflammatory responses and systematically describes multi-dimensional strategies for constructing non-inflammatory LNP, including structural optimization of ionizable lipids, replacement of PEG-lipids, and surface functionalization of LNP. On this basis, recent advances of non-inflammatory LNP in protein replacement therapy, gene editing, prophylactic vaccines, and cancer immunotherapy are further summarized to provide a theoretical reference for the design and application of safe and efficient non-inflammatory LNP delivery systems.

R944

国家自然科学基金青年科学基金项目（C类）（52503194）