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

Ischemic stroke therapy remains challenging due to a detrimental post-reperfusion inflammatory cascade that exacerbates neuronal damage, a process critically mediated by neutrophils and microglia. Neutrophils infiltrate the brain to release pro-inflammatory factors and neutrophil extracellular traps (NETs), while microglia become activated and amplify neuroinflammation. However, both cell types possess phenotypic plasticity that allows for immunomodulation toward repair. To address this, we developed a biomimetic nanoparticle strategy designed to reprogram these immune cells. Specifically, we encapsulated rosiglitazone into mPEG-PLA nanoparticles and further coated them with platelet membranes, obtaining a targeted nanoplatform termed pmPELA@R. In a mouse model of middle cerebral artery occlusion (MCAO), the platelet membrane coating markedly enhanced neutrophil targeting and improved brain accumulation of pmPELA@R. The released rosiglitazone activated PPAR-γ to polarize neutrophils toward the N2 phenotype and suppressed NETosis. Concurrently, the lactate generated from PLA degradation promoted microglial M2 polarization via enhanced histone lactylation. This dual modulation synergistically shifted the inflammatory microenvironment toward a reparative state, leading to enhanced neural tissue recovery. Our findings present a novel nanotherapeutic approach for precise immunomodulation in ischemic stroke.