Non-invasive CRISPR/Cas9 nanocapsules specifically edit α-synuclein for effective Parkinson’s disease treatment

Abstract

Parkinson’s disease (PD) is the most common movement disorders, affecting more than 1 % of the elderly population aged over 60 years old. Targeting the accumulation of the toxic protein α-synuclein (α-Syn) (SNCA) is a common therapeutic strategy for PD. CRISPR/Cas9 gene technology could provide an avenue to achieve reduced levels of this protein. However, the lack of effective and safe brain delivery vectors greatly hampers its applications for brain disorders. In this paper, we developed glucose directed single-particle nanocapsules that efficiently delivers CRISPR/Cas9 into targeted brain lesions to specifically edit the SNCA gene. Our CRISPR/Cas9 nanocapsules have a small size of 32 nm and formed with a polymeric shell which protects Cas9/sgRNA from enzymatic degradation. Benefitting from surface glucose decoration, our nanocapsules exhibited blood brain barrier (BBB) permeability and accumulation in brain lesions after intravenous administration. Additionally, CRISPR/Cas9 nanocapsules selectively reduced expression of the SNCA leading to down regulation of α-Syn protein, M1/M2 microglial re-polarization, amelioration of neuroinflammation and recovery of tryptophan hydroxylase (TH) in A53T transgenic mice. Importantly, CRISPR/Cas9 nanocapsules significantly improved performance of mice in a variety behavioral test with negligible side effects. Therefore, the CRISPR/Cas9 nanocapsules provides a versatile but potent platform for genetic engineering in brain disorders, especially genome mutations relevant to neuronal disease.