Lipid Metabolism‐Driven CNS Repair via Targeted EV Delivery of PAF to Neurons

Platelet-activating factor (PAF) is a potent phospholipid mediator with therapeutic potential in neuroregeneration, but its therapeutic application is hindered by rapid degradation and systemic proinflammatory effects. Here, we present an engineered extracellular vesicle (EV)-based delivery strategy that stabilizes and targets PAF to sites of hippocampal injury, restoring neuronal structure and cognitive function. EVs derived from EP4 antagonist-primed mesenchymal stem cells (GWEVs) exhibit enhanced secretion and selective enrichment of bioactive lipids, particularly PAF, which promotes neuroregeneration, attenuates gliosis and rescues spatial memory. Mechanistic studies reveal that PAF's therapeutic activity depends not on classical PTAFR engagement but on neuronal metabolism via PAF-acetylhydrolase (PAFAH), particularly the PAFAH1B1 subunit. The hydrolysis-resistant analogue MPAF fails to confer benefit, underscoring the requirement for enzymatic processing. To address translational needs, we developed a bioorthogonal click-labelling platform that enables real-time SPECT imaging of EV biodistribution while preserving function. GWEVs preferentially accumulate in injured hippocampi, confirming targeted delivery. This study defines a previously unrecognized lipid metabolism-dependent repair mechanism and demonstrates the feasibility of leveraging EVs for CNS-targeted delivery of labile lipid therapeutics. These findings offer a platform for advancing regenerative strategies in neurodegenerative diseases and traumatic brain injury.