Bioactive hydroxyl-terminated phosphorus dendrimers mediate protein/drug co-delivery for enhanced multi-target ischemic stroke therapy.

The treatment of ischemic stroke (IS) faces significant challenges due to the complex pathophysiology, which encompasses oxidative stress, neuroinflammation, and blood-brain barrier (BBB) dysfunction. Here, we report the development of a bioactive per se hydroxyl-terminated phosphorus dendrimer-based nanoplatform for protein/drug co-delivery to the ischemic brain. We show that through sequential physical complexation and loading, nanocomplexes (NCs) composed of phosphorus dendrimers, a protein drug of fibronectin (FN) with anti-inflammatory/antioxidant/angiogenic properties and a small molecular drug melatonin (MT) with antioxidant/mitochondrial protective activities can be formed. The created NCs have an average size of 146 nm, excellent stability, pH-sensitive MT release profile, desired cytocompatibility, and admirable BBB crossing ability via the dendrimer's high-density hydroxyl groups in vitro. The NCs can be conferred with active inflammatory targeting specificity through FN-mediated integrin αvβ3 binding to tackle three types of cells including microglia, neurons, and endothelial cells for potent anti-inflammatory/antioxidant/pro-angiogenic interventions of oxygen glucose deprivation/reperfusion-induced cells in vitro. In a rat IS model, the NCs incorporating full-active components are demonstrated to effectively accumulate in the ischemic brain, reduce infarct volume, restore mitochondrial function, mitigate neuronal apoptosis, promote vascular regeneration, and improve neurobehavioral outcomes. The developed full-active phosphorus dendrimer-based nanoplatform may represent an advanced nanomedicine formulation to tackle IS that enables combined modulation of neuroinflammation, neuroprotection, and vascular repair with a great clinical translation potential.