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Drug therapies targeting vasculature in metastatic cancer have not been highly effective and are therefore currently limited to an adjunctive role, such as in combination regimens. The development of novel, more effective therapeutic strategies with new mechanisms of action is therefore greatly needed. In a previous study, we reported a lipid nanoparticle (LNP)-based vascular-disrupting strategy utilizing cyclic RGD peptide-modified LNPs encapsulating small interfering RNA against Fas ligand (cRGD-LNP/siFasL). We combined this strategy for selective targeting of tumor endothelial cells with stimulator of interferon genes (STING) agonist-loaded LNPs (STING-LNPs). Here, we have demonstrated the potential of such combination therapy in treating lung metastases. We found that cRGD-LNPs accumulated in the vasculature within tumor colonies in the lung. A combination of cRGD-LNP/siFasL and STING-LNP induced significant antitumor effects in mouse models of Renca and 4T1 lung metastases. Moreover, this combination therapy reduced the vasculature within tumor colonies, with no obvious change in the surrounding normal lung tissue, indicating preferential vascular disruption. These findings demonstrate that the combination therapy exerts antitumor activity against lung metastases through tumor vascular disruption, indicating that such treatment is potentially a potent disrupter of the vascularity in metastatic tumors.