Tumor metastasis is responsible for chemotherapeutic failure and
cancer-related death. Moreover,
circulating tumor cell (CTC) clusters play a pivotal role in
tumor metastasis. Herein, we develop
cancer-specific
calcium nanoregulators to suppress the generation and circulation of CTC clusters by
cancer membrane-coated
digoxin (DIG) and
doxorubicin (DOX) co-encapsulated PLGA nanoparticles (CPDDs). CPDDs could precisely target the homologous primary
tumor cells and CTC clusters in blood and lymphatic circulation. Intriguingly, CPDDs induce the accumulation of intracellular Ca2+ by inhibiting Na+/K+-
ATPase, which help restrain cell-cell junctions to disaggregate CTC clusters. Meanwhile, CPDDs suppress the epithelial-mesenchymal transition (EMT) process, resulting in inhibiting
tumor cells escape from the primary site. Moreover, the combination of DOX and DIG at a mass ratio of 5:1 synergistically induces the apoptosis of
tumor cells. In vitro and in vivo results demonstrate that CPDDs not only effectively inhibit the generation and circulation of CTC clusters, but also precisely target and eliminate primary
tumors. Our findings present a novel approach for anti-
metastasis combinational
chemotherapy.