Phosphorus Dendrimers Co‐deliver Fibronectin and Edaravone for Combined Ischemic Stroke Treatment via Cooperative Modulation of Microglia/Neurons and Vascular Regeneration

Abstract The development of new multi‐target combination treatment strategies to tackle ischemic stroke (IS) remains to be challenging. Herein, a proof‐of‐concept demonstration of an advanced nanomedicine formulation composed of macrophage membrane (MM)‐camouflaged phosphorous dendrimer (termed as AK137)/fibronectin (FN) nanocomplexes (NCs) loaded with antioxidant edaravone (EDV) to modulate both microglia and neurons for effective IS therapy is showcased. The created MM@AK137‐FN/EDV (M@A–F/E) NCs with a mean size of 260 nm possess good colloidal stability, sustained EDV release kinetics, and desired cytocompatibility. By virtue of MM decoration, the M@A–F/E NCs can cross blood–brain barrier, act on microglia to exert the anti‐inflammatory (AK137 and FN) and antioxidative (FN and EDV) effects in vitro for oxidative stress alleviation, microglia M2 polarization, and reduction of pro‐inflammatory cytokine secretion, and act on neuron cells to be anti‐apoptotic. In a transient middle cerebral artery occlusion rat model, the developed M@A–F/E NCs can exert enhanced antioxidant/anti‐inflammatory/anti‐apoptotic therapeutic effects to comprehensively regulate the brain microenvironment and promote vascular regeneration to collaboratively restore the blood flow after ischemia‐reperfusion. The designed MM‐coated NCs composed of all‐active ingredients of phosphorous dendrimers, FN, and EDV that can fully regulate the brain inflammatory microenvironment may expand their application scope in other neurodegenerative diseases.