Xue Yonger, Wang Chang, Li Haoyuan, Du Shi, Zhong Yichen, Zhang Yuebao, Wang Siyu, Guo Kaiyuan, Hou Xucheng, Kang Diana D, Liu Zhengwei, Tian Meng, Cao Dinglingge, Deng Binbin, McComb David W, Markovic Tamara, Pan Jiayi, Borna Mandana, Nestler Eric J, Peng Paul C, Dong Yizhou
Icahn Genomics Institute, Precision Immunology Institute, Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
Division of Pharmaceutics & Pharmacology, College of Pharmacy, The Ohio State University, Columbus, OH, 43210, USA.
Adv Mater. 2025 May 3:e2417097. doi: 10.1002/adma.202417097.
Lipid nanoparticle-messenger RNA formulations have garnered significant attention for their therapeutic potential in infectious diseases, cancer and genetic disorders. However, effective mRNA delivery to the central nervous system (CNS) remains a formidable challenge. To overcome this limitation, a class of brain-targeting lipids (BLs) is developed by incorporating brain-targeting small molecules with amino lipids and formulated them with helper lipids to generate brain-targeting lipid nanoparticles (BLNPs) for mRNA delivery. Screening studies led to a lead formulation, TD5 BLNPs, outperforming FDA-approved DLin-MC3-DMA LNPs in delivering mRNA to the brain upon intrathecal injection. Specifically, a single intrathecal injection of TD5 BLNP-GFP mRNA led to GFP expression in 29.6% of neurons and 38.1% of astrocytes across the brain. In an Ai14 mouse model, TD5 BLNP-Cre recombinase mRNA treatment induced tdTomato expression in ≈30% of neurons and 40% of astrocytes across major brain regions. Notably, delivery of Cas9 mRNA/sgRNA complex using TD5 BLNPs achieved effective genome editing in the brain. Additionally, TD5 BLNPs showed comparable safety profiles to MC3 LNPs, indicating promising biocompatibility. Overall, this TD5 BLNP formulation effectively delivers mRNA to brain tissues via intrathecal injection and facilitates efficient expression in both neurons and astrocytes, presenting a potential strategy for treating CNS diseases.
脂质纳米颗粒-信使核糖核酸制剂因其在传染病、癌症和遗传疾病治疗方面的潜力而备受关注。然而，将信使核糖核酸有效递送至中枢神经系统（CNS）仍然是一项艰巨的挑战。为克服这一限制，通过将脑靶向小分子与氨基脂质结合，开发出一类脑靶向脂质（BLs），并与辅助脂质一起配制成用于信使核糖核酸递送的脑靶向脂质纳米颗粒（BLNPs）。筛选研究产生了一种先导制剂TD5 BLNPs，在鞘内注射后将信使核糖核酸递送至大脑方面，其表现优于美国食品药品监督管理局批准的DLin-MC3-DMA脂质纳米颗粒（LNPs）。具体而言，单次鞘内注射TD5 BLNP-GFP信使核糖核酸导致全脑29.6%的神经元和38.1%的星形胶质细胞中出现绿色荧光蛋白（GFP）表达。在Ai14小鼠模型中，TD5 BLNP-Cre重组酶信使核糖核酸处理在主要脑区约30%的神经元和40%的星形胶质细胞中诱导了tdTomato表达。值得注意的是，使用TD5 BLNPs递送Cas9信使核糖核酸/单向导核糖核酸（sgRNA）复合物在大脑中实现了有效的基因组编辑。此外，TD5 BLNPs显示出与MC3 LNPs相当的安全性，表明其具有良好的生物相容性。总体而言，这种TD5 BLNP制剂通过鞘内注射有效地将信使核糖核酸递送至脑组织，并促进其在神经元和星形胶质细胞中的高效表达，为治疗中枢神经系统疾病提供了一种潜在策略。
