Engineered Nanovesicles For Macrophage Reprogramming In Spinal Cord Injury

Intraspinal inflammation is a ubiquitous but poorly understood consequence of spinal cord injury (SCI). There is a well-established appreciation for both the reparative and pathological potential of activated macrophages however, the development of clinically viable, immunomodulatory therapies that can harness the reparative potential of macrophages while limiting pathology remains a critical challenge facing the SCI community. There is increasing evidence that endogenous extracellular vesicles, such as exosomes, released from immune cells as part of normal cell functions, have immunomodulatory properties in neurological disorders. While the therapeutic potential of cellular vesicle-based systems is well established in SCI, there are several technical limitations that must be overcome to make exosomes a viable translational treatment for SCI. Endogenous vesicles such as exosomes are currently being evaluated as potential immunotherapies; however, low yields and complex separation procedures still pose substantial barriers to their use. We have developed engineered vesicles derive from immune cells that can bidirectionally reprogram macrophages. The endogenous origin of nanovesicles is associated with low immunogenicity, intrinsic targeting ability toward macrophages, and inherent biocompatibility. The objective of this proposal is to advance our novel therapeutic platform by engineering vesicles to enhance targeting and functional capabilities for SCI. We will utilize vesicles generated from mesenchymal stem cells and macrophages and engineer them to optimize their therapeutic potential for reprogramming macrophages toward an anti-inflammatory phenotype.