Nano-Tumor interaction is the fundamental for cancer nanotherapy, and the cross-talking of nanomedicines with extracellular matrix (ECM) is increasingly considered essential. Here, we specially investigate the Nano-ECM interactivity using drug-free nanoparticulates (NPs) and high-metastatic cancer cells as the models. We discover with surprise that NPs closely bind to special types of ECM components, retraction fibers (RFs) and migrasomes, which locate at the rear of tumor cells during their migration. Such interaction is observed to alter cell morphology, limit cell motion range and change cell adhesion. Importantly, NPs are demonstrated in vitro to inhibit tumor cell removal, and their anti-metastasis potentiality is primarily confirmed in vivo. Mechanically, the NPs are found to coat and form a rigid shell on the surface of migrasomes and retraction fibers, via the interaction with lipid raft/caveolae substructures. With this, NPs block the recognition, endocytosis and elimination of migrasomes by their surrounding tumor cells. Thereby NPs interfere the cell-ECM interaction and reduce the promotion effect of migrasomes on cell movement. Besides, NPs trigger the expression alteration of proteins related to cell-cell adhesion and cytoskeleton organization, which also restricts the cell migration. In summary, all findings here provide a potential target for the nanomedicines of anti-tumor metastasis.