Astrocyte-targeted siRNA delivery by adenosine-functionalized LNP in mouse TBI model

Hai Xiao; Odmaa Amarsaikhan; Yunwang Zhao; Xiang Yu; Xin Hu; Shuqin Han; Chaolumen; Huricha Baigude

doi:10.1016/j.omtn.2023.102065

Astrocyte-targeted siRNA delivery by adenosine-functionalized LNP in mouse TBI model

Mol Ther Nucleic Acids. 2023 Oct 20:34:102065. doi: 10.1016/j.omtn.2023.102065. eCollection 2023 Dec 12.

Authors

Hai Xiao¹, Odmaa Amarsaikhan¹, Yunwang Zhao¹, Xiang Yu¹, Xin Hu¹, Shuqin Han¹, Chaolumen¹, Huricha Baigude¹

Affiliation

¹ Inner Mongolia Key Laboratory of Mongolian Medicinal Chemistry, School of Chemistry & Chemical Engineering, Inner Mongolia University, Hohhot, Inner Mongolia 010020, P.R. China.

Abstract

Traumatic brain injury (TBI) induces pro-inflammatory polarization of astrocytes and causes secondary disruption of the blood-brain barrier (BBB) and brain damage. Herein, we report a successful astrocyte-targeted delivery of small interfering RNA (siRNA) by ligand functionalized lipid nanoparticles (LNPs) formulated from adenosine-conjugated lipids and a novel ionizable lipid (denoted by Ad4 LNPs). Systemic administration of Ad4 LNPs carrying siRNA against TLR4 to the mice TBI model resulted in the specific internalization of the LNPs by astrocytes in the vicinity of damaged brain tissue. A substantial knockdown of TLR4 at both mRNA and protein levels in the brain was observed, which led to a significant decrease of key pro-inflammatory cytokines and an increase of key anti-inflammatory cytokines in serum. Dye leakage measurement suggested that the Ad4-LNP-mediated knockdown of TLR4 attenuated the TBI-induced BBB disruption. Together, our data suggest that Ad4 LNP is a promising vehicle for astrocyte-specific delivery of nucleic acid therapeutics.

Keywords: MT: Delivery Strategies; TBI; adenosine receptor; astrocyte; lipid nanoparticles; polarization; receptor-mediated endocytosis; siRNA delivery.