Matrix-bound nanovesicles recapitulate tissue-specific angiogenic properties of parent extracellular matrix with distinct miRNA profiles.

Decellularized extracellular matrix (dECM) exhibits tissue-specific pro- or anti-angiogenic effects. Previous studies have demonstrated that matrix-bound nanovesicles (MBVs) act as key bioactive components of dECM, replicating various biological functions such as anti-inflammatory and immunomodulatory effects. Building on this evidence, this study hypothesized that MBVs derived from cartilage and small intestinal submucosa (SIS) modulate angiogenesis through the selective packaging of miRNAs. Cartilage-derived MBVs (cMBVs) and SIS-derived MBVs (sMBVs) were isolated, characterized, and analyzed for their miRNA profiles using RNA sequencing and RT-qPCR validation. The interactions between MBVs and human umbilical vein endothelial cells (HUVECs) were assessed by examining proliferation, adhesion, migration, and tube formation in comparison to the parent ECM. Angiogenic modulation was further evaluated using a mouse Matrigel plug assay and a rabbit corneal neovascularization (NV) model. Our results demonstrated that anti-angiogenic miRNAs (e.g., miR-140-3p, miR-455-5p, and miR-148a-5p) were predominant in cMBVs, suppressing endothelial cell activity and angiogenesis, while pro-angiogenic miRNAs (e.g., miR-143-3p, miR-181a, and miR-21-5p) were prevalent in sMBVs, enhancing vessel formation. In vivo, cMBVs significantly inhibited vascular invasion and neovessel formation, whereas sMBVs promoted angiogenesis in both models. These findings confirm that MBVs reflect the tissue-specific angiogenic regulatory functions of their parent ECM, and highlight their potential as therapeutic tools for targeted modulation of angiogenesis in regenerative medicine and tissue engineering.