Matrix-bound nanovesicles isolated from decellularized tumors as platforms for targeting parent tumor cells and tumor-associated stromal cells

Matrix-bound nanovesicles (MBVs) are an emerging class of extracellular vesicles (EVs) that are integrated into the extracellular matrix (ECM). Tumor ECM-derived MBVs hold promise as platforms for targeted delivery of therapeutic agents to both parental tumor cells and surrounding stromal cells. In this study, a subcutaneous tumor model was established by implanting A549 human lung adenocarcinoma cells into immunodeficient mice. The mixed method was used to decellularize the tumor tissue, producing an ECM scaffold free of cellular components. Subsequently, MBVs were successfully isolated from the ECM of the decellularized tumors. Compared with tumor cell-derived liquid-phase EVs, acellular tumor MBVs were smaller in size and were demonstrated to transport proteins related to focal adhesion and protein binding. The in vitro binding affinity assays and cell culture experiments involving acellular tumor MBVs showed specific targeting affinity for ECM components, tumor cells, and tumor-associated stromal cells, including cancer-associated fibroblasts and tumor-associated macrophages. After loading of the drug doxorubicin, this platform selectively inhibited tumor cells and tumor-associated stromal cells both in vitro and in vivo. These results provide important insights for future research on the potential role of tumor ECM-derived MBVs in targeted cancer therapy and the modulation of premetastatic niches.