Modulation of microglial polarization by sequential targeting surface-engineered exosomes improves therapy for...

Area of Science:

• Neuroscience
• Biomedical Engineering
• Pharmacology

Background:

• Microglia play a crucial role in regulating neuroinflammation and neurofunction following ischemic stroke (IS).
• Targeting microglia in ischemic regions is vital for effective therapy and attenuating cerebral ischemic injury.
• Efficient drug accumulation in microglia is a key challenge in treating IS.

Purpose of the Study:

• To design and evaluate surface-engineered, multifunctional cascade-delivery drug carriers for targeting ischemic stroke.
• To enhance drug accumulation in microglia and induce neuroprotection of the neurovascular unit (NVU).
• To utilize mannose-conjugated luteolin-loaded platelet-derived exosomes (lut/man-pEXO) for targeted delivery.

Main Methods:

• Design of lut/man-pEXO as drug carriers targeting ischemic blood vessels and microglia.
• Evaluation of lut/man-pEXO's ability to bind to platelets and target ischemic injury sites.
• Assessment of mannose receptor-mediated selective binding to microglia and drug uptake.

Main Results:

• lut/man-pEXO demonstrated efficient targeting of ischemic cerebral vessels and injury sites.
• Superior microglia-targeting properties were observed due to mannose-mannose receptor affinity, increasing luteolin uptake.
• lut/man-pEXO modulated microglia from detrimental M1 to anti-inflammatory M2 phenotype, reducing infarct area, protecting the blood-brain barrier (BBB), and preventing astrocyte inflammation.

Conclusions:

• Surface-engineered lut/man-pEXO effectively targets microglia in ischemic stroke.
• This targeted delivery system enhances neuroprotection by modulating microglial activation and reducing ischemic damage.
• lut/man-pEXO represents a promising therapeutic strategy for ischemic stroke treatment.