Born, Louis JosephDespite the development of a variety of therapies, complex wounds resulting from disease, surgical intervention, or trauma remain a major source of morbidity. Extracellular vesicles (EVs) have recently emerged as an alternative approach to address this issue. In particular, EVs derived from mesenchymal stem/stromal cells (MSCs) have been shown to improve wound healing, especially via enhanced wound angiogenesis. However, despite their clearly established potential, EVs have limitations that limit clinical relevancy, including low potency and rapid clearance from the body. Additionally, the ability to sustainably deliver EVs may enhance their efficacy in wound healing. Here, we leveraged the capability of EVs to be engineered via producer cell modification to investigate the therapeutic potential of EVs from MSCs transfected to overexpress a well-established pro-angiogenic long non-coding RNA HOX transcript antisense RNA (HOTAIR). We established that HOTAIR was able to be successfully loaded into MSC EVs (HOTAIR-MSC EVs) and delivered to endothelial cells in vitro with increased functional angiogenic activity. HOTAIR-MSC EVs injected intradermally around excisional wounds also showed increased angiogenic activity in vivo in two different species of rodents and improved wound healing in diabetic mice. We further report biomaterial-enabled sustained release of EVs using injectable hydrogel nanoparticles containing a composite of thiolated hyaluronic acid, maleimide functionalized poly(ε-caprolactone), and polyethylene glycol tetraacryalte as well as 3D-printed hydrogel discs composed of gelatin methacrylate for topical application. EVs released from the formulation of both of these biomaterials retained angiogenic bioactivity. Nanoparticles containing HOTAIR-MSC EVs were injected intradermally around an excisional wound in diabetic mice and were able to increase angiogenesis and improve wound healing. EVs released from 3D-printed EV-loaded GelMa hydrogels retained bioactivity in an in vitro endothelial scratch assay. Overall, these data suggest increasing the content of lncRNA HOTAIR in MSC EVs as a promising wound healing therapeutic. Additionally, establishing a biomaterial-enabled sustained release therapeutic represents a promising translational product for clinical implementation.enDissertationBioengineeringMedicineNanotechnologyAngiogenesisBiomaterialsExosomesExtracellular VesiclesTherapeuticsWound Healing