Cao Dinglingge, Hou Xucheng, Wang Chang, Wang Siyu, Liu Zhengwei, Tian Meng, Guo Kaiyuan, Li Haoyuan, Kang Diana D, Zhong Yichen, Xue Yonger, Yu Changyue, Deng Binbin, Dong Yizhou
Icahn Genomics Institute, Precision Immunology Institute, Department of Immunology and Immunotherapy, Department of Oncological Sciences, Tisch Cancer Institute, Friedman Brain Institute, Biomedical Engineering and Imaging Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Division of Pharmaceutics and Pharmacology, College of Pharmacy, The Ohio State University, Columbus, OH, USA.
Sci Adv. 2025 Aug 15;11(33):eadw0730. doi: 10.1126/sciadv.adw0730. Epub 2025 Aug 13.
Efficient delivery of messenger RNA (mRNA) to the brain via systemic administration remains a challenge, primarily due to the blood-brain barrier. To address this challenge, we incorporated SR-57227, a ligand of serotonin [5-hydroxytryptamine type 3 (5-HT)] receptor, into the design of ionizable lipids to develop lipid nanoparticles (LNPs) for systemic mRNA delivery to the brain. OS4T LNP was identified as an optimized formulation based on multiple assays. Following systemic administration, OS4T LNP achieved over a 50-fold increase in mRNA translation within brain tissues compared to US Food and Drug Administration-approved Onpattro LNPs (DLin-MC3-DMA). In an orthotopic glioblastoma (GBM) mouse model, engineered interleukin-12 mRNA-loaded OS4T LNPs significantly suppressed tumor growth and improved overall survival. This study demonstrates OS4T LNP as a promising platform for brain mRNA delivery and highlights its potential for treating GBM and other central nervous system disorders.
通过全身给药将信使核糖核酸（mRNA）有效地递送至大脑仍然是一项挑战，主要原因是血脑屏障。为应对这一挑战，我们将血清素[5-羟色胺3型（5-HT）]受体的配体SR-57227纳入可电离脂质的设计中，以开发用于将mRNA全身递送至大脑的脂质纳米颗粒（LNP）。基于多种测定，OS4T LNP被确定为一种优化的制剂。全身给药后，与美国食品药品监督管理局批准的Onpattro LNP（DLin-MC3-DMA）相比，OS4T LNP在脑组织中的mRNA翻译增加了50倍以上。在原位胶质母细胞瘤（GBM）小鼠模型中，装载工程化白细胞介素-12 mRNA的OS4T LNP显著抑制肿瘤生长并改善总体生存率。这项研究证明OS4T LNP是用于大脑mRNA递送的一个有前景的平台，并突出了其治疗GBM和其他中枢神经系统疾病的潜力。
