Complexity, unpredictability and safety challenges of lipid nanoparticles

The lipid nanoparticle (LNP) platform for delivering modified messenger RNA (modRNA) represents a transformative yet inherently complex and unpredictable technology. This narrative review synthesizes multidisciplinary evidence to explore the physicochemical basis, biological interactions, pharmacodynamic uncertainties, and safety challenges associated with LNPs and LNP-modRNA interactions. We describe how LNP self-assembly gives rise to variable structures with inconsistent modRNA payloads, as well as dynamic protein corona formation and aggregation phenomena that complicate the reliable characterization of these systems. After injection, LNPs undergo rapid biotransformation, including PEG-lipid shedding, biodistribution, and cellular uptake, which current analytical techniques cannot fully capture. Importantly, endosomal escape, which leads to the disruption of the endosome and the release of the payload, occurs within a narrow time window, is often inefficient, and results in inconsistent delivery. In addition, lipid metabolites, cell membrane modulation, and adduct formation raise poorly characterized safety questions. This review summarizes published evidence to inform future safety evaluations. It does not provide medical or clinical recommendations.用于递送修饰信使RNA（modified messenger RNA, modRNA）的脂质纳米颗粒（lipid nanoparticle, LNP）平台，是一项兼具变革性且本质上复杂且不可预测的技术。本叙述性综述整合多学科证据，旨在探讨脂质纳米颗粒及其与修饰信使RNA复合物相互作用的理化基础、生物相互作用、药效学不确定性与安全挑战。我们将阐述脂质纳米颗粒的自组装过程如何产生载荷量不均一的可变结构，以及会加剧该体系可靠表征难度的动态蛋白冠形成与聚集现象。注射后，脂质纳米颗粒会发生快速生物转化，包括PEG脂质脱落、生物分布与细胞摄取，而当前分析技术尚无法完全捕捉这些过程。 尤为重要的是，介导内体破裂并释放载荷的内体逃逸，仅发生于狭窄的时间窗内，且通常效率低下，会导致递送效果不均一。此外，脂质代谢物、细胞膜调控与加合物形成均带来了表征尚不充分的安全问题。本综述总结已发表的相关证据，为未来的安全评估提供参考，本综述不提供医疗或临床建议。