Targeted exosome coating gene-chem nanocomplex as “nanoscavenger” for clearing α-synuclein and immune activation of Parkinson’s disease

Abstract

The most critical problem in the treatment of neurodegenerative diseases is brain neuronal protection, which can be overcome by clearing pathological substances and regulating the immune environment. In the above treatment strategies, the traditional poor drug delivery problem is inevitable. Here, we show an engineering core-shell hybrid system named rabies virus glycoprotein (RVG) peptide–modified exosome (EXO) curcumin/phenylboronic acid-poly(2-(dimethylamino)ethyl acrylate) nanoparticle/small interfering RNA targeting SNCA (REXO-C/ANP/S). It is a nanoscavenger for clearing α-synuclein aggregates and reducing their cytotoxicity in Parkinson’s disease neurons. The motor behavior of Parkinson’s disease mice is substantially improved after REXO-C/ANP/S treatment. In particular, we demonstrate that REXO-C/ANP/S is also a nanoscavenger for clearing immune activation due to its natural immature dendritic cell EXO coating. Our findings show that REXO-C/ANP/S may serve as a platform for neurodegenerative diseases treatment.

Exosomal delivery of therapeutic modulators through the blood–brain barrier; promise and pitfalls

“…To overcome some immunological issues related to this technology, the hybridization of exosomes with these synthetic complexes was successfully applied to drug delivery to the brain [ 224 ]. REXO-C/ANP/S is a novel gen-chem/exosome nano scavenger which coloaded hydrophilic gene and hydrophobic small-molecule drugs for curing high ROS environment in Parkinson disease (PD) [ 225 , 226 ].…”

Extracellular Vesicles for the Diagnosis and Treatment of Parkinson’s Disease

“…In another study, Liu and co-workers engineered a nano-scavenger called “REXO-C/ANP/S” for delivering drugs through the BBB into neurons [ 91 ]. The system comprised a shell called REXO and a reactive oxygen species (ROS)-responsive gene-chem coloaded core or nanocomplex.…”

“…The nanocomplex comprised an amphiphilic polymer encapsulating the hydrophobic drug curcumin and siRNA targeting SNCA gene involved in alpha-synuclein production. Such an engineered delivery system could cross the BBB and target and release drugs directly to dopaminergic neurons in a high ROS milieu [ 91 ]. When administered in a mouse model of PD, REXO-C/ANP/S targeted TH+ dopaminergic neurons in the substantia nigra and enhanced α-syn clearance, which resulted in reduced motor deficits.…”

Parkinson’s Disease: A Nanotheranostic Approach Targeting Alpha-Synuclein Aggregation

“…Notably, another recent study designed a multifunctional NPs which can deliver both RNAi therapy and drug. Liu et al (2020) designed an engineering core-shell hybrid system named rabies virus glycoprotein (RVG) peptide–modified exosome (EXO) curcumin/phenylboronic acid-poly[2-(dimethylamino)ethyl acrylate] nanoparticle/siRNA targeting SNCA (REXO-C/ANP/S), which can act as a nanoscavenger and SNCA inhibitor. Nanocomplexes coloaded with siRNA and curcumin were coated with REXO, exosomes modified with RVG peptide, which could specifically bind to the acetylcholine receptor and facilitate entry across BBB and neurons.…”

“…Nanocomplexes coloaded with siRNA and curcumin were coated with REXO, exosomes modified with RVG peptide, which could specifically bind to the acetylcholine receptor and facilitate entry across BBB and neurons. Since curcumin is a neuroprotective drug known to inhibit α-syn aggregation, the combination of siRNA and curcumin work synergistically to down regulate α-syn expression, inhibit α-syn aggregation and reduce ROS production, which subsequently help to reduce the cytotoxicity of α-syn aggregates in dopaminergic neurons ( Sharma and Nehru, 2018 ; Liu et al, 2020 ). All these studies illustrated the promising result of nano delivery of RNAi therapy in mouse model, thus further studies will be required to validate their uses in humans.…”