Engineered extracellular vesicles derived from primary M2 macrophages with anti-inflammatory and neuroprotective properties for the treatment of spinal cord injury.

BACKGROUND: Uncontrollable inflammation and nerve cell apoptosis are the most destructive pathological response after spinal cord injury (SCI). So, inflammation suppression combined with neuroprotection is one of the most promising strategies to treat SCI. Engineered extracellular vesicles with anti-inflammatory and neuroprotective properties are promising candidates for implementing these strategies for the treatment of SCI. RESULTS: By combining nerve growth factor (NGF) and curcumin (Cur), we prepared stable engineered extracellular vesicles of approximately 120 nm from primary M2 macrophages with anti-inflammatory and neuroprotective properties (Cur@EVs-cl-NGF). Notably, NGF was coupled with EVs by matrix metalloproteinase 9 (MMP9)-a cleavable linker to release at the injured site accurately. Through targeted experiments, we found that these extracellular vesicles could actively and effectively accumulate at the injured site of SCI mice, which greatly improved the bioavailability of the drugs. Subsequently, Cur@EVs-cl-NGF reached the injured site and could effectively inhibit the uncontrollable inflammatory response to protect the spinal cord from secondary damage; in addition, Cur@EVs-cl-NGF could release NGF into the microenvironment in time to exert a neuroprotective effect against nerve cell damage. CONCLUSIONS: A series of in vivo and in vitro experiments showed that the engineered extracellular vesicles significantly improved the microenvironment after injury and promoted the recovery of motor function after SCI. We provide a new method for inflammation suppression combined with neuroprotective strategies to treat SCI.

Nerve growth factor loaded macrophage-derived nanovesicles for inhibiting neuronal apoptosis after spinal cord injury.

Spinal cord injury (SCI) is an extremely destructive central nervous system lesion. Studies have shown that NGF can promote nerve regeneration after SCI. However, it cannot produce the desired effect due to its stability in the body and is difficulty in passing through the blood-brain barrier. In this study, we prepared nanovesicles derived from macrophage membrane encapsulating NGF (NGF-NVs) as a drug carrier for the treatment of SCI. Cell experiments showed that NGF-NVs were effectively taken up by PC12 cells and inhibited neuronal apoptosis. In vivo imaging experiments, a large quantity of NGF was delivered to the injured site with the aid of the good targeting of NVs. In animal experiments, NGF-NVs improved the survival of neurons by significantly activating the PI3K/AKT signaling pathway and had good behavioral and histological recovery effects after SCI. Therefore, NVs are a potential drug delivery vector for SCI therapy.