Zeng Jin-Yue, Lingesh Shonya, Krishnan Nithiyaa Bala, Loong Brandon Seow Yi, Liu Min, Chen Qingfeng, Yang Yi Yan
Bioprocessing Technology Institute (BTI), Agency for Science, Technology and Research (A*STAR), 20 Biopolis Way, Centros #06-01, Singapore, 138668, Singapore.
Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A*STAR), Singapore, 138673, Singapore.
Small Methods. 2025 Jun;9(6):e2401712. doi: 10.1002/smtd.202401712. Epub 2025 Apr 21.
Effective delivery of lipid nanoparticles (LNPs)-based mRNA vaccines to antigen presenting cells (APCs) is important for eliciting potent immune responses. However, most LNPs-based mRNA vaccines usually suffer from insufficient accumulation in APCs due to the lack of active targeting capability, leading to the limited efficacy and the need for high injection dose. In this study, a series of cholesterol-derived mannopolypeptide (CPSM) and cholesterol-conjugated mannose (CM) derivatives is synthesized to prepare mannosylated LNPs for efficient mRNA delivery. The co-assembly of CPSM and/or CM is demonstrated with ionizable lipid, helper lipid, and cholesterol into LNPs provides the colloidal stability of LNPs, and endows LNPs the ability to target APCs. The leading mannosylated LNPs including CPSM-LNP and CM/CPSM-LNP exhibit efficient mRNA transfection ability in dendritic cells and mice. Specifically, CPSM-LNP and CM/CPSM-LNP show preferential accumulation in the lymph nodes compared with commercial ALC-LNP from Pfizer/BioNTech's COVID-19 mRNA vaccine formulation. This study presents a straightforward yet effective strategy to synthesize cholesterol-derived mannopolypeptides and prepare mannosylated LNPs for successful in vivo mRNA delivery.
将基于脂质纳米颗粒（LNP）的mRNA疫苗有效递送至抗原呈递细胞（APC）对于引发强效免疫反应至关重要。然而，由于缺乏主动靶向能力，大多数基于LNP的mRNA疫苗通常在APC中积累不足，导致疗效有限且需要高注射剂量。在本研究中，合成了一系列胆固醇衍生的甘露糖多肽（CPSM）和胆固醇共轭甘露糖（CM）衍生物，以制备用于高效mRNA递送的甘露糖化LNP。CPSM和/或CM与可电离脂质、辅助脂质和胆固醇共组装成LNP，提供了LNP的胶体稳定性，并赋予LNP靶向APC的能力。领先的甘露糖化LNP，包括CPSM-LNP和CM/CPSM-LNP，在树突状细胞和小鼠中表现出高效的mRNA转染能力。具体而言，与辉瑞/生物NTech新冠mRNA疫苗配方中的市售ALC-LNP相比，CPSM-LNP和CM/CPSM-LNP在淋巴结中表现出优先积累。本研究提出了一种直接而有效的策略，用于合成胆固醇衍生的甘露糖多肽并制备甘露糖化LNP，以成功实现体内mRNA递送。
