Wang Jiapeng, Chen Renjie, Xie Yongyi, Qin Xuanting, Zhou You, Xu Chuanshan
Department of Medical Imageology, The Second Clinical College of Guangzhou Medical University, Guangzhou 511436, China.
State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences, Guangzhou Medical University, Guangzhou 511436, China.
Pharmaceutics. 2025 Jun 20;17(7):803. doi: 10.3390/pharmaceutics17070803.
mRNA-based drug development is revolutionizing tumor therapies by enabling precise cancer immunotherapy, tumor suppressor gene restoration, and genome editing. However, the success of mRNA therapies hinges on efficient delivery systems that can protect mRNA from degradation and facilitate its release into the cytoplasm for translation. Despite the emergence of lipid nanoparticles (LNPs) as a clinically advanced platform for mRNA delivery, the efficiency of endo/lysosomal escape still represents a substantial bottleneck. Here, we summarize the intracellular fate of mRNA-loaded LNPs, focusing on their internalization pathways and processing within the endo-lysosomal system. We also discuss the impact of endo-lysosomal processes on mRNA delivery and explore potential strategies to improve mRNA escape from endo-lysosomal compartments. This review focuses on molecular engineering strategies to enhance LNP-mediated endo/lysosomal escape by optimizing lipid composition, including ionizable lipids, helper lipids, cholesterol, and PEGylated lipids. Additionally, ancillary enhancement strategies such as surface coating and shape management are discussed. By comprehensively integrating mechanistic insights into the journey of LNPs within the endo-lysosome system and recent advances in lipid chemistry, this review offers valuable inspiration for advancing mRNA-based cancer therapies by enabling robust protein expression.
基于信使核糖核酸（mRNA）的药物开发正在彻底改变肿瘤治疗方法，实现精确的癌症免疫治疗、肿瘤抑制基因恢复和基因组编辑。然而，mRNA疗法的成功取决于高效的递送系统，该系统能够保护mRNA不被降解，并促进其释放到细胞质中进行翻译。尽管脂质纳米颗粒（LNPs）作为一种临床先进的mRNA递送平台已经出现，但内体/溶酶体逃逸效率仍然是一个重大瓶颈。在这里，我们总结了负载mRNA的LNPs的细胞内命运，重点关注它们的内化途径和在内体-溶酶体系统中的处理过程。我们还讨论了内体-溶酶体过程对mRNA递送的影响，并探索改善mRNA从内体-溶酶体区室逃逸的潜在策略。本综述重点关注通过优化脂质组成（包括可电离脂质、辅助脂质、胆固醇和聚乙二醇化脂质）来增强LNP介导的内体/溶酶体逃逸的分子工程策略。此外，还讨论了诸如表面涂层和形状管理等辅助增强策略。通过将机制见解全面整合到LNPs在内体-溶酶体系统中的旅程以及脂质化学的最新进展，本综述为通过实现强大的蛋白质表达推进基于mRNA的癌症治疗提供了宝贵的灵感。
