Targeted Inhibition of Tumor Inflammation and Tumor-Platelet Crosstalk by Nanoparticle-Mediated Drug Delivery Mitigates Cancer Metastasis

Sowing malignant cells (the "seeds" of metastasis) to engraft secondary sites requires a conducive premetastatic niche (PMN, the "soil" of metastasis). Inflammation and tumor associated platelet (TAP) has been hijacked by primary tumors to induce PMN "soil" in distant organs, as well as facilitate the dissemination of "seeds". This study reports a combinatory strategy with activated platelet-targeting nanoparticles to aim at the dynamic process of entire cancer metastasis, which exerts robust antimetastasis efficacy by simultaneously inhibiting tumor inflammation and tumor-platelet crosstalk. Our results reveals that the PSN peptide (a P-selectin-targeting peptide) modification enriched the accumulation of nanoparticles in primary tumor, pulmonary PMN, and metastases via capturing activated platelet. Such characteristics contribute to the efficient inhibition on almost every crucial and consecutive step of the metastasis cascade by retarding epithelial-mesenchymal transition (EMT) progression within tumors, specifically blocking the tumor-platelet crosstalk to remove the platelets "protective shield" around disseminated "seeds", and reversing the inflammatory microenvironment to interfere with the "soil" formation. Consisting of inflammation inhibiting and TAP impeding nanoparticles, this approach prominently reduces various metastasis in abscopal lung, including spontaneous metastasis, disseminated tumor cells metastasis, and post-operative metastasis. This work provides a generalizable nanoplatform of parallel inflammation disturbance and tumor-TAP crosstalk blockade to resist metastatic tumors.