Blockade of Platelets Using Tumor-Specific NO-Releasing Nanoparticles Prevents Tumor Metastasis and Reverses Tumor Immunosuppression

The tumor microenvironment maintains a sufficient immunosuppressive state owing to the existence of the immunosuppressive factors. The most prominent such factor is transforming growth factor β (TGF-β), which is mainly provided by platelets. Moreover, platelets have been shown to be the main accomplice in assisting tumor metastasis. Therefore, blocking tumor-associated platelets is endowed with functions of enhancing immunity and reducing metastasis. Herein, we designed a tumor microenvironment-responsive nitric oxide (NO) release nanoparticle, Ptx@AlbSNO, which was able to specifically and safely co-deliver the antiplatelet agent NO and the chemotherapeutic agent paclitaxel (Ptx) into tumor tissues and inhibit platelet–tumor cell interactions. We discovered that Ptx@AlbSNO could successfully block tumor-specific platelet functions, thereby suppressing the process of tumor epithelial–mesenchymal transition (EMT), preventing platelet adhesion around circulating tumor cells (CTCs) and reducing distant metastasis. In vivo studies demonstrate that the co-delivery of NO and Ptx can suppress primary tumor growth. With the ability to effectively inhibit activated platelets and TGF-β secretion in tumors, Ptx@AlbSNO can enhance intratumoral immune cell infiltration to reverse the immunosuppressive tumor microenvironment.