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Heterogeneous distribution of drug inside tumor is ubiquitous, causing regional insufficient chemotherapy, which might be the hotbed for drug resistance, tumor cell repopulation and metastasis. Herein, we verify, for the first time, that heterogeneous drug distribution induced insufficient chemotherapy would accelerate the process of epithelial mesenchymal transition (EMT), consequently resulting in the promotion of tumor metastasis. To eliminate the insufficient chemotherapy promoted metastasis, we conceived a co-delivery strategy by hydroxyethyl starch-polylactide (HES-PLA) nanoparticle, in which DOX and TGF-β receptor inhibitor, LY2157299 (LY), were administered together. In vitro and in vivo studies demonstrate that this co-delivery strategy can simultaneously suppress primary tumor and distant metastasis. Further study on immunofluorescence images of primary tumor verifies that low dose of DOX exasperates the EMT process, whereas the co-delivery nanoparticle can dramatically inhibit the progression of EMT. We reveal the impact of heterogeneous drug distribution on tumor metastasis and develop an effective co-delivery strategy to suppress the metastasis, providing guidance for clinical cancer therapy.Heterogeneous drug distribution inside tumor induces regional insufficient chemotherapy, which accelerates EMT process, consequently promoting tumor metastasis. Co-delivery nanoparticle can suppress EMT process via blocking TGF-β pathway, inhibiting tumor metastasis.