Intranasal blood-brain barrier bypass enables sequential mitochondria-targeted bioengineered nanolamellar system for ischemic stroke therapy.

Summary

The authors engineered a hybrid biomembrane-coated black phosphorus nanosheet system (MM@BPPF) delivering sequential therapeutic agents to restore neuronal mitochondrial function and modulate microglia after ischemia. Intranasal administration bypassed the BBB and increased brain/mitochondrial targeting, demonstrating therapeutic benefit in ischemia-reperfusion models.

Key Findings

• MM@BPPF combines microglia- and mitochondria-derived membranes on black phosphorus nanosheets loaded with PolyMet and FTY720.
• Intranasal administration bypasses the BBB and increases accumulation in injured brain regions and neuronal mitochondria.
• Sequential actions of BP NSs, PolyMet, and FTY720 restore mitochondrial function and modulate microglial polarization, improving outcomes in ischemia-reperfusion models.

Clinical Implications

If validated in larger preclinical and early-phase clinical studies, this approach could enable noninvasive intranasal therapies to limit ischemic brain injury by restoring mitochondrial function and modulating neuroinflammation.

Limitations

• Translation to humans remains untested; safety, dosing, and long-term effects of BP NSs and membrane coatings require study.
• Potential immunogenicity or off-target effects of hybrid biomembranes were not fully characterized.

Future Directions

Advance to rigorous preclinical toxicology and biodistribution studies, optimize dose/regimen, and pursue early-phase clinical trials to test safety and proof-of-concept in stroke patients.