Engineered Exosomes Derived From Primary M2 Macrophages With Anti-inflammatory And Neuroprotective Properties For The Treatment of Spinal Cord Injury.

Abstract 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 exosomes with anti-inflammatory and neuroprotective properties are promising candidates for the implementation of this strategies for the treatment of SCI. Results: By combining nerve growth factor (NGF) and curcumin (Cur), we prepared stable engineered exosomes of approximately 120 nm from primary M2 macrophages with anti-inflammatory and neuroprotective properties (Cur@EXs-cl-NGF). Notably, NGF was coupled with EXs by matrix metalloproteinase 9 (MMP9)-cleavable linker to accurately release at the injured site. Through targeted experiments, we found that these exosomes could actively and effectively accumulate at the injured site of SCI mice, which greatly improved the bioavailability of the drugs. Subsequently, Cur@EXs-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@EXs-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 exosomes 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.