Establishing a pre-metastatic niche (PMN) in secondary organs is a prerequisite for cancer metastases. Despite advances in cancer therapy, the efficient inhibition of PMN formation remains a clinical challenge. Recent advances in understanding the specific characteristics of PMN and advances in nanotechnology have provided hope for manipulating their microenvironments. A series of nanostrategies have been designed to eliminate the PMN, including the removal of pro-metastatic exosomes from the bloodstream for excretion via the intestines, the targeting and scavenging of myeloid-derived suppressor cells, fibroblasts, and critical extracellular matrix components, and the elimination of circulating tumor cells prior to colonization in distant organs. This review summarizes the underlying mechanisms of PMN formation, highlights the anti-PMN efficacy of currently reported nanostrategies, and underlines the unresolved questions.