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 (MI), we previously engineered an infusible decellularized extracellular matrix (iECM) biomaterial that reduces vascular permeability and exerts immunomodulatory and pro-reparative effects. To probe the heterogenous contents of iECM and its contribution to infarct localization and downstream biological function, we separated iECM into high and low molecular weight (MW) components. Though mass spectrometry showed similar compositions, biochemical analysis and transmission electron microscopy revealed higher sGAG content within the nanofibrillar high MW, while the globular low MW had more exposed functional groups. These differences translated to a higher binding efficiency of the high MW to ECM proteins and cell surface receptors under flow, while the low MW drove the reduction in vascular permeability. Neither component alone achieved the infarct retention levels of complete iECM, showing that the two components exhibit dependent infarct localization and both are necessary for iECM's overall function. Via single‑nucleus RNA sequencing, both components elicited comparable immunomodulatory and pro‑reparative transcriptional profiles, suggesting that the similarity in composition likely drives the transcriptional response. These findings elucidate the material properties of an intravascularly deliverable ECM biomaterial and how those properties relate to downstream biological behavior, enabling future work investigating nanomaterial mimicry and improvements in material processing and potency.