Reversing neuroinflammation in ischemic stroke through efferocytotic phenotype reprogramming with polymeric...

Area of Science:

• Neuroscience
• Immunology
• Biomaterials Science

Background:

• Ischemic stroke triggers harmful inflammation mediated by neutrophils and microglia.
• These immune cells, while damaging, have potential for immunomodulation towards repair.
• Current therapies face challenges in managing post-reperfusion inflammation.

Purpose of the Study:

• To develop a biomimetic nanoparticle system for targeted immunomodulation in ischemic stroke.
• To reprogram neutrophils and microglia towards a reparative phenotype.
• To enhance neural tissue recovery following ischemic stroke.

Main Methods:

• Encapsulation of rosiglitazone within mPEG-PLA nanoparticles, coated with platelet membranes (pmPELA@R).
• Utilizing a mouse model of middle cerebral artery occlusion (MCAO).
• Assessing neutrophil and microglial polarization and inflammatory markers.

Main Results:

• Platelet membrane coating improved nanoparticle targeting to neutrophils and brain accumulation.
• Rosiglitazone activated PPAR-γ, polarizing neutrophils to N2 phenotype and suppressing NETosis.
• PLA degradation-induced lactate promoted M2 microglial polarization via histone lactylation, enhancing neural recovery.

Conclusions:

• The pmPELA@R nanoplatform effectively modulates neutrophils and microglia in ischemic stroke.
• This dual immunomodulatory strategy shifts the brain environment towards repair.
• Presents a novel nanotherapeutic approach for precise treatment of ischemic stroke.