Rocket-Inspired Sequentially Targeted Nanotherapeutics for Mitochondrial Regulation and Inflammatory Reprogramming in...

Area of Science:

• Biomedical Engineering
• Neuroscience
• Pharmacology

Background:

• Mitochondrial dysfunction is a key factor in cerebral ischemia-reperfusion injury (CIRI).
• The blood-brain barrier (BBB) limits effective pharmacological treatment for CIRI.
• Targeting mitochondrial homeostasis is crucial for managing CIRI.

Purpose of the Study:

• To develop a novel nanoplatform for targeted drug delivery across the BBB in CIRI.
• To restore mitochondrial homeostasis and mitigate neuronal damage in CIRI.
• To investigate a sequential targeting strategy for enhanced therapeutic efficacy.

Main Methods:

• Development of a neutrophil-hitchhiking, biomimetic nanoplatform (NeuM@Mdivi-1).
• Utilizing neutrophil chemotaxis to bypass the BBB and target the ischemic penumbra.
• Employing a MMP9-triggered surface transformation for intracellular drug release of Mdivi-1.

Main Results:

• NeuM@Mdivi-1 successfully infiltrated the ischemic penumbra by co-opting neutrophils.
• The nanoplatform enabled precise intracellular release of Mdivi-1, inhibiting Drp1-mediated mitochondrial fission.
• Therapeutic intervention suppressed the Drp1/mtDNA/cGAS-STING signaling axis, mitigating neuronal ferroptosis and preserving neuronal viability.

Conclusions:

• NeuM@Mdivi-1 offers a sophisticated therapeutic paradigm for CIRI management.
• The nanoplatform effectively restores mitochondrial homeostasis and reduces inflammation.
• This approach demonstrates potential for treating BBB-restricted neurological disorders.