School of Chemistry & Chemical Engineering, Inner Mongolia University, Hohhot, Inner Mongolia 010020, P.R. China.
J Med Chem. 2024 Aug 8;67(15):13217-13230. doi: 10.1021/acs.jmedchem.4c01176. Epub 2024 Jul 20.
Pro-inflammatory polarization of microglia and astrocytes results in neuroinflammation and blood-brain barrier (BBB) disruption after a primary traumatic brain injury (TBI). Herein, we demonstrate that the dual-ligand functionalized lipid nanoparticles (AM31 LNPs) were actively and specifically internalized by microglia and astrocytes via mannose receptor (MR)- and adenosine receptor (AR)-mediated endocytosis, respectively, in a mouse model of TBI. Systemic administration of AM31 LNPs carrying siRNA against p65 resulted in internalization by the glial cells in the peri-infarct region and a robust knockdown of p65 at both mRNA and protein levels in these cells, leading to significant down-regulation of key pro-inflammatory cytokines and up-regulation of key anti-inflammatory cytokines. AM31 LNP-mediated silencing of p65 ameliorated TBI-induced BBB disruption. Our data proved that AM 31 LNP is a promising vehicle for RNA therapeutics for targeting microglia and astrocytes in neural disorder.
小胶质细胞和星形胶质细胞的促炎极化导致原发性创伤性脑损伤 (TBI) 后神经炎症和血脑屏障 (BBB) 破坏。在此，我们证明了双配体功能化脂质纳米颗粒 (AM31 LNPs) 通过甘露糖受体 (MR) 和腺苷受体 (AR) 介导的内吞作用分别被 TBI 小鼠模型中的小胶质细胞和星形胶质细胞主动且特异性地内化。携带针对 p65 的 siRNA 的 AM31 LNPs 的系统给药导致亲梗死区的神经胶质细胞内化，以及这些细胞中 p65 的 mRNA 和蛋白水平的强烈敲低，导致关键促炎细胞因子的显著下调和关键抗炎细胞因子的上调。AM31 LNP 介导的 p65 沉默改善了 TBI 引起的 BBB 破坏。我们的数据证明，AM31 LNP 是一种有前途的 RNA 治疗载体，可用于针对神经紊乱中的小胶质细胞和星形胶质细胞。
