Cancer Metastasis Blockage by Exosome-Neutrophil Nanocoupler

Most malignancy patients die of cancer cell metastasis, in which tumor-derived exosomes (TDEs) play a critical role by priming premetastatic niche formation, since most TDEs carry cancer-specific biomolecules such as cytokines, nucleic acids, and lipids through the peripheral blood to distant organs. Thus, blocking the TDEs' migration in the vascular system is an especially promising antimetastasis strategy; unfortunately, however, existing treatments have shown limited efficacy. In this study, we present an exosome-neutrophil binding strategy using a reactive oxygen species-producing nanocoupler to eliminate intravascular exosomes via neutrophil endocytosis. As a paradigm, we investigated the clearance of pancreatic tumor-derived exosomes (PTDEs) due to the high metastatic potential of pancreatic ductal adenocarcinomas. Specifically, a PTDEs-neutrophils nanocoupler has been obtained by asymmetrically modifying one side of an iron-aluminum layered double hydroxide (Fe/Al LDH) nanosheet with Ly6G antibody targeting neutrophils, and the opposite side with EphA2 antibody targeting PTDE, which binds PTDEs onto the membranes of neutrophils. Resultantly, PTDEs in peripheral blood can be eliminated through the phagocytic activity of neutrophils together with the oxidative damage against cancer-specific biomolecules within PTDEs by the Fe/Al LDH-enhanced neutrophil respiratory burst, ultimately inhibiting the metastasis of pancreatic ductal adenocarcinomas. This study introduces a novel strategy for eliminating TDEs as key metastatic drivers, offering a promising approach for blocking metastasis in aggressive malignancies, with pancreatic cancer as the paradigm, with promising potential for clinical translation.