2026-08-27 東京科学大学
脂質ナノ粒子の肝類洞壁による捕捉を抑制するメカニズム
＜関連情報＞
- https://www.isct.ac.jp/ja/news/jb5hx9i6u0nj
- https://pubs.acs.org/ancac3/article/doi/10.1021/acsnano.6c08403/5268353/2-arm-PEG-Oligocations-Transiently-Shield-the
2本鎖PEGオリゴカチオンは、肝類洞を一時的に遮蔽し、mRNA搭載脂質ナノ粒子に基づく肝臓での発現を軽減する 2-arm-PEG-Oligocations Transiently Shield the Liver Sinusoids to Mitigate Off-Target Hepatic Expression of mRNA Lipid Nanoparticles
Anjaneyulu Dirisala;Bhaskar Chatterjee;Nguyen Bui Thao Le;Kazuko Toh;Miki Matsui-Masai;Saed Abbasi;Xueying Liu;Theofilus A. Tockary;Nan Qiao;Junichi Ishikawa;Jumpei Norimatsu;Yuki Mochida;Shigeto Fukushima;Makoto Oba;Kazunori Kataoka;Satoshi Uchida
ACS Nano Published:August 18, 2026
DOI:https://doi.org/10.1021/acsnano.6c08403
Abstract
Ionizable lipid nanoparticles (iLNPs) are powerful platforms for mRNA-based vaccines and immunotherapies; however, their intrinsic liver tropism compromises both safety and efficacy. Off-target hepatic protein expression from delivered mRNA raises safety concerns, and hepatic clearance limits efficient iLNP delivery to target organs. In this study, we address these challenges in mouse models by stealth-coating the liver sinusoidal endothelial (LSE) wall, the primary gateway for nanoparticle entry into the liver. Specifically, oligocations conjugated with two-armed PEG (2-arm-PEG-oligocations), a clinically relevant material used in oligonucleotide delivery trials, were employed to transiently anchor PEG to the LSE wall with balanced affinity, ensuring robust coating followed by gradual biliary clearance. This approach reduced hepatic protein expression from iLNPs, subsequently administered either systemically or locally, by more than 10-fold. Importantly, the strategy preserved iLNP accumulation in the spleen, a key target organ for vaccines, effectively redirecting iLNPs from the liver to the spleen. Consequently, in vaccine applications, preinjection of the 2-arm-PEG-oligocation preserved or even enhanced vaccination efficacy while minimizing concerns associated with antigen expression in the liver. In applications involving cytokine mRNA therapy, specifically intratumoral interleukin-12 (IL-12) mRNA administration, systemic preinjection of the 2-arm-PEG-oligocation successfully reduced off-target hepatic IL-12 expression and subsequent systemic IL-12 exposure, while maintaining antitumor efficacy. Collectively, these results demonstrate that LSE-wall stealth coating is a generalizable strategy to improve both the safety and efficacy of iLNP-based mRNA vaccines and immunotherapies.
