A Multidimensional Engineering Strategy Reprograms Microglia via Targeted and Sustained-Release Extracellular...

Area of Science:

• Biomaterials Science
• Neuroscience
• Regenerative Medicine

Background:

• Spinal cord injury (SCI) causes neuroinflammation, hindering recovery.
• Mesenchymal stem cell-derived extracellular vesicles (EVs) show therapeutic promise but face challenges in bioactivity, targeting, and release.
• Current strategies need improvement for effective clinical translation in SCI treatment.

Purpose of the Study:

• To engineer advanced extracellular vesicles (EVs) for enhanced spinal cord injury (SCI) repair.
• To overcome limitations of traditional EV therapies, including low bioactivity and poor targeting.
• To develop a stimuli-responsive delivery system for sustained and targeted EV release at the injury site.

Main Methods:

• Engineered EVs (Tetramethylpyrazine-pretreated and Angiopep-2 modified) were encapsulated in a ROS-responsive hydrogel (Ang-TEVs@Gel).
• The construct was evaluated for lesion accumulation, microglial uptake, and therapeutic efficacy in a mouse SCI model.
• Mechanism of action investigated via microRNA delivery (miR-664a-3p) to modulate microglial phenotype and signaling pathways (PI3K-AKT-mTOR).

Main Results:

• Ang-TEVs@Gel demonstrated efficient accumulation and selective uptake by microglia at the SCI site.
• The treatment reprogrammed microglia, promoting myelin debris clearance and reducing inflammation.
• Significant improvements in axonal regeneration, remyelination, and motor function recovery were observed in SCI mice.

Conclusions:

• This multidimensional engineering strategy enhances EV therapeutic potential for SCI.
• The combination of preconditioning, active targeting, and stimuli-responsive delivery offers a promising approach for CNS repair.
• The developed Ang-TEVs@Gel system provides a blueprint for advanced EV-based therapies for neurological disorders.