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

## TL;DR

This study shows how engineered extracellular vesicles can deliver a lipid molecule called PAF to the brain, promoting neuron repair and cognitive recovery after injury.

## Contribution

A novel EV-based delivery system for PAF that enables targeted CNS repair through neuronal lipid metabolism.

## Key findings

- GWEVs stabilize PAF and deliver it to injured hippocampi, restoring neuronal structure and cognitive function.
- PAF's therapeutic effect relies on neuronal metabolism via PAFAH1B1, not classical receptor activation.
- A bioorthogonal labeling platform enables real-time tracking of EVs without compromising their function.

## Abstract

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.

Encapsulation within GWEVs stabilizes platelet‐activating factor (PAF), prevents peripheral inflammation and enables targeted delivery across the blood–brain barrier. In the brain, GWEVs localize to injury sites and deliver PAF to neurons, where PAFAH1B1‐dependent cytoskeletal remodelling promotes repair, supporting GWEVs as a therapeutic platform for neural regeneration.