# A Hierarchical Microglial-Targeting Nanoplatform for the Therapy of Parkinson’s Disease by Modulating Mitochondrial Dysfunction

## TL;DR

A new nanoplatform targets microglia in Parkinson’s Disease to repair mitochondrial dysfunction and reduce inflammation.

## Contribution

A dual-targeting nanosystem was designed to deliver wedelolactone to microglia for PD therapy.

## Key findings

- The nano-delivery system increased blood half-life and brain distribution by evading immune clearance.
- It specifically targeted microglia, repaired mitochondrial structure, and reduced pro-inflammatory cytokines.
- The system improved the inflammatory microenvironment in PD mouse models.

## Abstract

Background: Mitochondrial dysfunction in microglia is an important pathogenic factor inducing the onset of Parkinson’s Disease (PD). To address this challenge, a novel hierarchical nano-delivery system was developed to deliver a PD therapeutic agent, wedelolactone (WED) to modulate mitochondrial dysfunction. Methods: The nano-delivery system (WED@RBCm-B6&RAP12-NPs) was coated with red blood membrane (RBCm) to avoid immune clearance and conjugated with the BBB-penetrating peptide CGHKAKGPRK (B6) and the microglia targeting peptide EAKIEKHNHYQK (RAP12). Results: The experimental results demonstrated that this novel nano-delivery system could increase its half-life in blood circulation effectively via evading immune recognition and clearance and enhanced its brain distribution by synergistic effect of B6 and RAP12. By specifically targeting microglia in PD mouse brain, the system increased pyruvate dehydrogenase (PDH) activity, leading to mitochondrial structural repair, reduced secretion of pro-inflammatory cytokines, and improved the inflammatory microenvironment. Conclusions: The result first designed and synthesis a dual targeting drug delivery system WED@RBCm-B6&RAP12-NPs which significantly alleviated mitochondrial dysfunction and warranted further study to develop therapeutic agent for PD treatment.