Drack, A.; Tran, A. H.; rai, a.; Rnjak-Kovacina, J.; Greening, D.

The transplantation of stem cell-derived extracellular vesicles (EVs) holds promise for tissue repair and regeneration, but scalable production and effective delivery to target tissue remain major challenges. Here, we present a biomaterial platform that combines high-yield, scalable nanovesicles (NVs) - EV mimetics derived from human induced pluripotent stem cells - with an adhesive silk hydrogel patch for localized and sustained delivery. We show that this platform enables efficient NV encapsulation via visible light crosslinking and supports controlled release over short (2 days), intermediate (7 days), and extended (up to 28 days) periods, while maintaining adhesion to heart tissue. Importantly, the sustained delivery of NVs for 3 days in vitro results in promoting anti-fibrotic cell remodeling and significant functional recovery of primary myofibroblast activation, modulating integrin signaling, actomyosin organization, and cell-matrix adhesion networks. Finally, we demonstrate biocompatibility, retention, and anti-fibrotic function of the patch in a murine ischemia-reperfusion injury model. Thus, we establish the proof-of-principle that dityrosine silk hydrogels can be used as a strategy to encapsulate and deliver NVs to the heart, thus offering an innovative delivery platform for NVs.