Lung metastasis is the major cause of death in patients with triple negative breast cancer (TNBC),an aggressive subtype of breast cancer with no effective therapy at present.It has been proposed that dual-targeted therapy,ie,targeting chemotherapeutic agents to both tumor vasculature and cancer cells,may offer some advantages.The present work was aimed to develop a dual-targeted synergistic drug combination nanomedicine for the treatment of lung metastases of TNBC.Thus,Arg-Gly-Asp peptide (RGD)-conjugated,doxorubicin (DOX) and mitomycin C (MMC) co-loaded polymer-lipid hybrid nanoparticles (RGD-DMPLN) were prepared and characterized.The synergism between DOX and MMC and the effect of RGD-DMPLN on cell morphology and cell viability were evaluated in human MDA-MB-231 cells in vitro.The optimal RGD density on nanoparticles (NPs) was identified based on the biodistribution and tumor accumulation of the NPs in a murine lung metastatic model of MDA-MB-231 cells.The microscopic distribution of RGD-conjugated NPs in lung metastases was examined using confocal microscopy.The anticancer efficacy of RGDDMPLN was investigated in the lung metastatic model.A synergistic ratio of DOX and MMC was found in the MDA-MB-231 human TNBC cells.RGD-DMPLN induced morphological changes and enhanced cytotoxicity in vitro.NPs with a median RGD density showed the highest accumulation in lung metastases by targeting both tumor vasculature and cancer cells.Compared to free drugs,RGD-DMPLN exhibited significantly low toxicity to the host,liver and heart.Compared to non-targeted DMPLN or free drugs,administration of RGD-DMPLN (10 mg/kg,iv) resulted in a 4.7-fold and 31-fold reduction in the burden of lung metastases measured by bioluminescence imaging,a 2.4-fold and 4.0-fold reduction in the lung metastasis area index,and a 35％ and 57％ longer median survival time,respectively.Dual-targeted RGD-DMPLN,with optimal RGD density,significantly inhibited the progression of lung metastasis and extended host survival.