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.
Keyphrases
- traumatic brain injury
- nucleic acid
- toll like receptor
- cancer therapy
- resting state
- inflammatory response
- severe traumatic brain injury
- white matter
- immune response
- blood brain barrier
- functional connectivity
- cerebral ischemia
- fatty acid
- quantum dots
- hyaluronic acid
- oxidative stress
- small molecule
- drug delivery
- nuclear factor
- photodynamic therapy
- type diabetes
- electronic health record
- brain injury
- skeletal muscle
- diabetic rats
- binding protein
- subarachnoid hemorrhage
- protein protein
- big data
- high resolution
- endothelial cells