posted on 2023-12-19, 08:13authored byJan Tuma, Yu-Ju Chen, Michael G. Collins, Abhik Paul, Jie Li, Hesong Han, Rohit Sharma, Niren Murthy, Hye Young Lee
Neurological disorders are often debilitating conditions
with no
cure. The majority of current therapies are palliative rather than
disease-modifying; therefore, new strategies for treating neurological
disorders are greatly needed. mRNA-based therapeutics have great potential
for treating such neurological disorders; however, challenges with
delivery have limited their clinical potential. Lipid nanoparticles
(LNPs) are a promising delivery vector for the brain, given their
safer toxicity profile and higher efficacy. Despite this, very little
is known about LNP-mediated delivery of mRNA into the brain. Here,
we employ MC3-based LNPs and successfully deliver Cre mRNA and Cas9
mRNA/Ai9 sgRNA to the adult Ai9 mouse brain; greater than half of
the entire striatum and hippocampus was found to be penetrated along
the rostro-caudal axis by direct intracerebral injections of MC3 LNP
mRNAs. MC3 LNP Cre mRNA successfully transfected cells in the striatum
(∼52% efficiency) and hippocampus (∼49% efficiency).
In addition, we demonstrate that MC3 LNP Cas9 mRNA/Ai9 sgRNA edited
cells in the striatum (∼7% efficiency) and hippocampus (∼3%
efficiency). Further analysis demonstrates that MC3 LNPs mediate mRNA
delivery to multiple cell types including neurons, astrocytes, and
microglia in the brain. Overall, LNP-based mRNA delivery is effective
in brain tissue and shows great promise for treating complex neurological
disorders.