Transferrin-Modified\nCarprofen Platinum(IV) Nanoparticles\nas Antimetastasis Agents with Tumor Targeting, Inflammation Inhibition,\nEpithelial–Mesenchymal Transition Suppression, and Immune Activation\nProperties

The inflammatory microenvironment is a central driver\nof tumor\nmetastasis, intimately associated with the promotion of epithelial–mesenchymal\ntransition (EMT) and immune suppression. Here, transferrin-modified\ncarprofen platinum(IV) nanoparticles Tf-NPs@CPF<sub>2</sub>–Pt(IV)\nwith promising antiproliferative and antimetastatic properties were\ndeveloped, which activated by inhibiting inflammation, suppressing\nEMT, and activating immune responses besides causing DNA injury. The\nnanoparticles released the active ingredient CPF<sub>2</sub>–Pt(IV)\nin a sustained manner and offered enhanced pharmacokinetic properties\ncompared to free CPF<sub>2</sub>–Pt(IV) in vivo. Additionally,\nthey possessed satisfactory tumor targeting effects via the transferrin\nmotif. Serious DNA damage was induced with the upregulation of γ-H2AX\nand P53, and the mitochondria-mediated apoptotic pathway Bcl-2/Bax/caspase3\nwas initiated. Inflammation was alleviated by inhibiting COX-2 and\nMMP9 and decreasing inflammatory cytokines TNF-α and IL-6. Subsequently,\nthe EMT was reversed by inhibiting the Wnt/β-catenin pathway.\nFurthermore, the antitumor immunity was provoked by blocking the immune\ncheckpoint PD-L1 and increasing CD3<sup>+</sup> and CD8<sup>+</sup> T lymphocytes in tumors.