A full-active phosphorus dendron-based nanomedicine alleviates ischemic stroke through multi-target immunomodulation and neuroprotection.

Designing nanomedicines with full-active components to overcome the blood-brain barrier (BBB) and achieve multi-target immunomodulation and neuroprotection for effective ischemic stroke (IS) treatment still remains a great challenge. Herein, we developed bioactive per se hydroxyl-terminated phosphorus dendron (C17G1-OH) micelles to co-deliver fibronectin (FN), an anti-inflammatory and anti-oxidative protein drug and docosahexaenoic acid (DHA), an anti-inflammatory and neuroprotection drug. The constructed DHA@C17G1-OH/FN micelles with a mean size of 254.5 nm are cytocompatible, exhibit desired stability, and can be efficiently phagocytosed by brain endothelial cells and microglia. Importantly, the high density of peripheral hydroxyl groups and FN-mediated integrin recognition enable the multifunctional micelles to penetrate BBB and achieve targeted accumulation at the IS region, thus suppressing neuroinflammation by microglia M2 polarization and oxidative stress alleviation, while rescuing neuronal apoptosis by balancing mitochondrial homeostasis. In a rat IS model, the DHA@C17G1-OH/FN micelles significantly reduce the infarct area, restore neurological behavior, neutralize inflammation and attenuate neuronal damage by multi-target immunomodulation, neuroprotection and repairment of the damaged BBB through FN-promoted angiogenesis of endothelial cells. The developed full-active phosphorus dendron-based nanomedicine synergistically modulates microglia, neurons, and endothelial cells for synergistic immune modulation and neuroprotection, and may represent an advanced formulation for effective IS alleviation.