Wang Sizhen, Zheng Jianyu, Zhou Jiao, Jiang Weiwei, Chen Zhendong, Wu Xiaoxian, Guo Beibei, Wu Yanfeng, Yang Feng
National Key Laboratory of Immunity and Inflammation & School of Pharmacy, Naval Medical University, Shanghai, 200433, China.
National Key Laboratory of Immunity and Inflammation & Institute of Immunology, College of Basic Medical Sciences, Naval Medical University, Shanghai, 200433, China.
Mater Today Bio. 2025 Jul 19;34:102107. doi: 10.1016/j.mtbio.2025.102107. eCollection 2025 Oct.
Lipid nanoparticles (LNPs) have emerged as a pivotal carriers for enhancing mRNA therapeutics, particularly in antitumor therapy. However, achieving robust antigen expression remains a major challenge due to limitations in precise targeted delivery and inefficient endosomal escape. In this study, we constructed an ambidextrous LNP to achieve robust tumor-specific antigen expression through targeted cell delivery and enhanced endosomal escape of mRNA-LNPs. To improve endosomal escape, we synthesized a novel pH-responsive PEGylated lipid designed to synergistically enhance membrane fusion effect with ionizable lipids, thereby optimizing the translation of the desired antigen. This is accomplished by promoting the early endosomal escape and endosomal recycling transport. For precise delivery of mRNA-LNPs to dendritic cells, we employed a mannose-modified PEGylated lipid that targets mannose receptors. Our results demonstrated that the combination of mannose-directed targeting and pH-mediated endosomal escape significantly enhances antigen translation and expression, leading to a vigorous immune response, as validated by both in vitro and in vivo experiments. This ambidextrous strategy advances the formulation of LNPs for precise mRNA delivery and effective antigen encoding, facilitating the development of mRNA vaccines in the field of antitumor immunology.
脂质纳米颗粒（LNPs）已成为增强mRNA疗法的关键载体，尤其是在抗肿瘤治疗中。然而，由于精确靶向递送的局限性和内体逃逸效率低下，实现强大的抗原表达仍然是一个重大挑战。在本研究中，我们构建了一种双功能LNP，通过靶向细胞递送和增强mRNA-LNPs的内体逃逸来实现强大的肿瘤特异性抗原表达。为了改善内体逃逸，我们合成了一种新型的pH响应性聚乙二醇化脂质，旨在与可电离脂质协同增强膜融合效果，从而优化所需抗原的翻译。这是通过促进早期内体逃逸和内体循环运输来实现的。为了将mRNA-LNPs精确递送至树突状细胞，我们采用了一种靶向甘露糖受体的甘露糖修饰聚乙二醇化脂质。我们的结果表明，甘露糖导向的靶向作用和pH介导的内体逃逸相结合，显著增强了抗原翻译和表达，引发了强烈的免疫反应，体外和体内实验均验证了这一点。这种双功能策略推动了用于精确mRNA递送和有效抗原编码的LNPs制剂的发展，促进了抗肿瘤免疫学领域mRNA疫苗的开发。
