Metastasis causes high mortality of breast cancer, and the inability of drug delivery to metastatic sites remains a crucial challenge for antimetastasis therapy. Herein, we report that inflammatory monocytes loading legumain-activated nanoparticles can actively target lung metastases and initiate metastasis-specific intelligent drug release for antimetastasis therapy. The cytotoxic mertansine is conjugated to poly(styrene-co-maleic anhydride) with a legumain-sensitive peptide and self-assembled into nanoparticles (SMNs), and then loaded into inflammatory monocytes to prepare the SMNs-loaded monocytes delivery system (M-SMNs). M-SMNs would be in living state in circulation to ensure their active targeting to lung metastases, and responsively damaged at the metastatic sites upon the differentiation of monocytes into macrophages. The anticancer drugs are intelligently released from M-SMNs as free drug molecules and drug-loaded microvesicles, resulting in considerable inhibition on the proliferation, migration, and invasion activities of metastatic 4T1 breast cancer cells. Moreover, M-SMNs significantly improve the delivery to lung metastases and penetrate the metastatic tumors, thus producing a 77.8% inhibition of lung metastases. Taken together, our findings provide an intelligent biomimetic drug delivery strategy via the biological properties of inflammatory monocytes for effective antimetastasis therapy.