Abstract

Engineered Stem Cell-Derived Extracellular Vesicles: Promising Theranostics for Tissue Regeneration

Aijun Wang, Associate Professor, Director of Translational Research, Innovation and Entrepreneurship, University of California-Davis

Stem cells and stem cell-derived extracellular vesicles (EVs) have remarkable therapeutic potential for various diseases and conditions. We have developed technologies to engineer and manufacture clinical-grade placenta-derived mesenchymal stem cells (PMSCs), and have shown that PMSCs and PMSC-derived EVs (PMSC-EVs) hold significant promise in tissue regeneration applications. However, the therapeutic efficacy of EVs has been largely limited due to their degradation and rapid diffusion after administration, hindering their translational applications. We developed a series of technologies to engineer EVs to improve their therapeutic function. One example is the new generation of collagen-binding EVs, which were designed and produced by chemically conjugating a collagen-binding peptide SILY to EVs (SILY-EVs) via click chemistry. This design enables the binding of EVs to collagen in the extracellular matrix (ECM) and form an EV-ECM complex that significantly improves EVs' in situ retention and therapeutic efficacy after transplantation. We thoroughly optimized the EV surface chemical modification methods and characterized the engineered EVs using a series of in vitro bulk and single EV characterization approaches and further in a mouse hind limb ischemia model in vivo. We confirmed that SILY-EVs presented longer in situ retention, suppressed inflammatory responses, and significantly augmented muscle regeneration and vascularization, compared to the unmodified EVs. With the broad distribution of collagen in various tissues and organs, SILY-EVs hold promise to improve the therapeutic efficacy of EV-mediated treatment in a wide range of diseases and disorders. Moreover, SILY-EVs possess the potential to functionalize collagen-based biomaterials and deliver therapeutic agents for regenerative medicine applications.