An infusible decellularized extracellular matrix material binds to vasculature in infarcted myocardium and induces pro-reparative gene expression following acute myocardial infarction through inherent avidity and bioactive signaling.

To treat acute myocardial infarction immediately after reperfusion, we previously engineered an intravascularly infusible decellularized extracellular matrix (iECM) biomaterial that exerts immunomodulatory and pro-reparative effects. However, the impact of the heterogeneous contents of iECM on infarct localization and downstream biological function is unknown. Using liquid chromatography, iECM is separated into a high molecular weight (MW) and low MW component. Mass spectrometry confirms compositional similarity, while biochemical assays and transmission electron microscopy highlight differences in biochemical features and structure, revealing a nanofibrillar high MW component and a globular peptide low MW. Quartz crystal microbalance studies show binding of each component to basal lamina ECM proteins and endothelial cell surface receptors under flow, demonstrating the specificity of ECM biomaterials to permeable vasculature. In vivo, the low MW component reduces vascular permeability, while neither component alone achieves the retention levels of complete iECM. Using single-nucleus RNA sequencing to probe bioactivity, both components elicited comparable angiogenic, immunomodulatory, and pro-reparative transcriptional programs. These findings illustrate that highly coupled materials and biological characterization uncover fundamental behaviors and properties of iECM biomaterials. Additionally, we show the unique binding behavior of iECM to the gaps of permeable vasculature, which could be exploited for future nanomaterial design.