The liver is the primary site of metastasis for gastrointestinal cancers and is a location highly susceptible to the establishment of metastasis in numerous other primary cancers, including breast, lung, and pancreatic cancers. The current standard of care typically consists of primary tumor resection and systemic administration of potent but toxic chemotherapeutics, yielding a minimal improvement in the median survival rate. CXCL12, a chemokine, is a key factor for activating the migration/survival pathways of CXCR4 cancer cells and for recruiting immunosuppressive cells to areas of inflammation. Therefore, reducing CXCL12 concentrations within the liver has the potential to decrease tumor and immunosuppressive cell activation/migration within the liver. However, because of off-target toxicities associated with systemic administration of anti-CXCL12 therapies, transient and liver-specific expression of a CXCL12 trap is necessary. To address this challenge, we developed a lipid calcium phosphate nanoparticle optimized for delivering plasmid DNA, encoding an engineered CXCL12 protein trap, to the nucleus of liver hepatocytes. This pCXCL12-trap formulation yielded transient (4 days) liver-specific expression, which greatly decreased the occurrence of liver metastasis in two aggressive liver metastasis models, including colorectal [CT-26(FL3)] and breast (4T1) cancers. Subsequent studies in an aggressive human colorectal liver metastasis model (HT-29) decreased the establishment of liver metastasis more effectively than did systemic administration of the CXCL12 protein trap and to a level comparable to a high-dose regimen of a potent CXCR4 antagonist (AMD3100).