Shell-Sheddable Polymeric Micelles Alleviate Oxidative Stress and Inflammation for Enhanced Ischemic Stroke Therapy

Area of Science:

• Neuroscience
• Biomaterials Science
• Pharmacology

Background:

• Resveratrol shows neuroprotective effects against ischemic stroke by modulating microglial polarization.
• The blood-brain barrier (BBB) limits resveratrol's efficacy in treating ischemic stroke.
• Microglia play a critical role in neuroinflammation and stroke pathology.

Purpose of the Study:

• To develop a stepwise targeting nanoplatform for enhanced resveratrol delivery to microglia mitochondria for ischemic stroke treatment.
• To overcome the BBB penetration challenge and improve therapeutic efficacy.
• To investigate the potential of this nanoplatform in reversing microglial phenotype and alleviating oxidative stress.

Main Methods:

• Fabrication of pH-responsive poly(ethylene glycol)-acetal-polycaprolactone-poly(ethylene glycol) (PEG-Acetal-PCL-PEG) micelles.
• Modification of micelles with cRGD for BBB penetration and triphenylphosphine (TPP) for mitochondrial targeting.
• In vitro and in vivo evaluation of BBB crossing, cellular uptake, and therapeutic effects in an ischemic stroke model.

Main Results:

• The cRGD modification facilitated effective BBB penetration via transcytosis.
• Detachment of the long PEG shell in acidic lysosomes exposed TPP for mitochondrial targeting within microglia.
• Enhanced resveratrol delivery to microglia mitochondria effectively scavenged reactive oxygen species (ROS), reduced inflammation, and reversed M1 to M2 microglial polarization.

Conclusions:

• The developed stepwise targeting nanoplatform significantly enhances resveratrol delivery and efficacy for ischemic stroke therapy.
• This strategy offers a promising approach to overcome BBB limitations and target intracellular organelles in microglia.
• The nanoplatform demonstrates potential for treating ischemia-reperfusion injury by modulating neuroinflammation and oxidative stress.