Angiopep-2-engineered extracellular vesicles derived from spinal cord injury-responsive brown adipose tissue for targeted neuroinflammation modulation

Spinal cord injury (SCI) affects over 15 million people globally with no curative treatments available. While primary mechanical trauma initiates tissue damage, secondary pathological cascades including neuroinflammation and mitochondrial dysfunction expand the injury. Current clinical interventions focus only on symptom management without restoring neural function. This study investigates the role of brown adipose tissue (BAT) in SCI repair through extracellular vesicles (EVs). Using ¹⁸F-FDG PET/CT imaging, this study discovered significant BAT activation post-SCI, peaking at 7 days, which was confirmed by histological analysis. Activated BAT increased EV secretion, with secreted EVs being selectively taken up by spinal microglia. miRNA sequencing identified miR-692 as the key EV cargo that silenced pro-inflammatory Spp1 gene in microglia, promoting their anti-inflammatory polarization and enhancing neuronal survival. Further development of a targeted delivery system using Angiopep2-modified BAT-EVs encapsulated in GelMA hydrogel for sustained release at injury sites significantly reduced lesion volume and improved functional recovery. The research establishes the BAT-EV-microglia axis as crucial for SCI repair and presents a promising biomaterial-enhanced EV therapy for SCI treatment, marking a significant advancement in regenerative medicine.