Injectable extracellular vesicle-released self-assembling peptide nanofiber hydrogel as an enhanced cell-free therapy for tissue regeneration.

Mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) have shown great potential for tissue repair, but their therapeutic capacity is limited by rapid clearance and short half-life. Herein, we purposed a hydrogel-based slow release strategy to enhance the therapeutic potency of EVs. A matrix metalloproteinase-2 (MMP2) sensitive self-assembling peptide (KMP2) hydrogel was used for the local delivery of MSC-EVs. The structure and controlled release properties of the KMP2 hydrogel were analyzed. The effects of the EV-loaded KMP2 hydrogel (KMP2-EVs) on cell apoptosis, inflammation and angiogenesis were evaluated in mice with renal ischemia-reperfusion (I/R) injury. In vitro, KMP2 formed a cross-linked nanofiber hydrogel to encapsulate MSC-EVs. KMP2 showed greater degradation and EV release in response to MMP2. The released EVs had similar structures and bioactivities as fresh, isolated EVs. In vivo, I/R mice treated with KMP2-EVs showed improved renal function by reducing tubular cell apoptosis, pro-inflammatory cytokine expression, and macrophage infiltration than mice receiving either EVs or KMP2. Moreover, KMP2-EVs showed better efficacy on promoting endothelial cell proliferation and angiogenesis than KMP2 or EVs alone, which subsequently decreased chronic renal fibrosis in I/R mice. This study highlighted that the EV-released KMP2 hydrogel is a promising cell-free therapy for tissue repair.