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

Area of Science:

• Biomaterials Science
• Nanotechnology
• Neuroscience

Background:

• Ischemic stroke (IS) presents complex challenges including oxidative stress, neuroinflammation, and blood-brain barrier (BBB) dysfunction.
• Current treatments are limited by the intricate pathophysiology of IS.

Purpose of the Study:

• To develop a novel nanoplatform for co-delivering protein and small molecular drugs to the ischemic brain.
• To create a system capable of modulating neuroinflammation, providing neuroprotection, and promoting vascular repair for IS treatment.

Main Methods:

• Fabrication of hydroxyl-terminated phosphorus dendrimer-based nanocomplexes (NCs) loaded with fibronectin (FN) and melatonin (MT).
• Characterization of NCs for size, stability, drug release, cytocompatibility, and BBB crossing ability in vitro.
• Evaluation of NCs' targeting specificity and therapeutic effects on oxygen-glucose deprivation/reperfusion-induced cells in vitro.
• Assessment of NCs' efficacy in a rat IS model, including infarct volume, mitochondrial function, apoptosis, vascular regeneration, and neurobehavioral outcomes.

Main Results:

• Developed stable NCs (146 nm) with pH-sensitive MT release and good BBB crossing ability.
• Demonstrated FN-mediated targeting of microglia, neurons, and endothelial cells for anti-inflammatory, antioxidant, and pro-angiogenic effects in vitro.
• Showed significant reduction in infarct volume, improved mitochondrial function, decreased neuronal apoptosis, enhanced vascular regeneration, and better neurobehavioral outcomes in a rat IS model.
• NCs effectively accumulated in the ischemic brain.

Conclusions:

• The developed phosphorus dendrimer-based nanoplatform enables effective co-delivery of therapeutic agents to the ischemic brain.
• This nanoplatform shows potential for combined modulation of neuroinflammation, neuroprotection, and vascular repair in IS.
• The formulation holds promise for clinical translation in treating ischemic stroke.