Physicochemical remodeling of osteoblast-derived decellularized matrix by tumor extracellular vesicles creates a pro-metastatic biointerface.

Recapitulating the dynamic physicochemical remodeling of the extracellular matrix (ECM) interface remains a central hurdle in modeling tumor bone metastasis, as conventional in vitro systems inadequately capture these complex cell-material interactions. To address this, we engineered a biomimetic decellularized ECM (dECM) biointerface by priming osteoblasts with breast cancer-derived extracellular vesicles (EVs) prior to decellularization, thereby generating a matrix that mirrors the tumor-conditioned osteoblastic phenotype. Relative to matrices conditioned with low-metastatic EVs (L-dECM), those programmed with highly metastatic EVs (H-dECM) displayed pronounced physicochemical deviations-namely, a disorganized collagen architecture, augmented mechanical stiffness, and a proteomic signature enriched for metastatic pathways. In vitro interrogation of this bio-instructive interface revealed that the H-dECM not only potentiated breast cancer cell adhesion, proliferation, and migration, but also provoked epithelial-mesenchymal transition (EMT) and upregulated the VEGF/CXCR4 axis. In vivo, implanted H-dECM scaffolds served as potent biomimetic decoys, markedly facilitating early tumor cell recruitment and colonization. Mechanistically, these malignancy-associated phenotypes were sustained by the altered physicochemical cues of the H-dECM interface, which acted through ITGB1-mediated activation of the FAK/ERK mechanotransduction cascade. Collectively, this EV-programmed dECM platform constitutes a robust biomaterial-based model that faithfully captures the tumor-conditioned matrix milieu, offering a powerful tool for dissecting matrix-driven mechanobiology in metastatic bone disease.