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Bio-clickable, small extracellular vesicles-COCKTAIL therapy for ischemic stroke
Khan Haroon1, Huitong Ruan2, Haoran Zheng1
1Shanghai Jiao Tong University Affiliated Sixth People's Hospital, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai 200030, China.
Summary
Researchers developed a novel small extracellular vesicle (sEV) delivery system, sEVs-COCKTAIL, for targeted delivery of the neuroprotective peptide NR2B9c to the brain. This innovative approach enhances therapeutic efficacy for ischemic stroke by improving brain targeting and reducing neuronal damage.
Area of Science:
- Neuroscience
- Biotechnology
- Drug Delivery
Background:
- Treating ischemic stroke with large molecules is hindered by blood-brain barrier penetration.
- Small extracellular vesicles (sEVs) offer a natural, non-immunogenic delivery platform but lack efficient brain targeting.
- NR2B9c is a potent neuroprotective peptide requiring enhanced delivery for stroke therapy.
Purpose of the Study:
- To develop and evaluate a targeted delivery system for NR2B9c to treat ischemic stroke.
- To enhance the brain targeting efficiency of small extracellular vesicles (sEVs).
- To assess the neuroprotective potential of NR2B9c-loaded sEVs in vitro and in vivo.
Main Methods:
- Coupling rabies virus glycoprotein 29 to sEVs via bio-orthogonal click chemistry to create bio-clickable sEVs.
- Loading NR2B9c into modified sEVs to generate sEVs-COCKTAIL.
- In vitro studies using primary neurons and Neuro-2a cells under oxygen-glucose deprivation.
- In vivo studies using a transient middle cerebral artery occlusion (tMCAO) model in rodents.
Main Results:
- Bio-clickable sEVs demonstrated selective neuronal uptake, sparing glial cells.
- sEVs-COCKTAIL significantly reduced reactive oxygen species and apoptosis in vitro.
- In vivo studies showed enhanced brain targeting, prolonged half-life, and reduced stroke injury.
- Treatment improved behavioral recovery and decreased neuronal apoptosis post-tMCAO.
- NR2B9c targeted neurons, inhibited NMDA receptor-mediated oxidative stress, and modulated apoptosis-related proteins.
Conclusions:
- The developed sEVs-COCKTAIL system provides efficient and biocompatible targeted delivery of NR2B9c across the blood-brain barrier.
- This targeted delivery approach holds significant promise for mitigating ischemic stroke injury.
- The study presents a viable strategy for enhancing the therapeutic potential of neuroprotective agents for stroke treatment.
