T cell-mimicking platelet-drug conjugates

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•Platelets act as “Trojan horse” killers to target and inhibit tumor metastasis •Platelet-drug conjugates mimic the natural cytotoxic mechanisms of T cells •Engineered platelets explore the potential of immune-independent cell therapies Cancer metastasis is the leading cause of cancer-related deaths. The indispensable role of platelets in tumor metastasis inspires the targeted delivery strategy by using platelet-drug conjugates (PDCs). Here, we armed platelets with granzyme B and perforin nanocomplexes to suppress cancer metastasis by leveraging the natural cytotoxic mechanism of T cells. Upon systemic administration, PDCs naturally capture circulating tumor cells (CTCs) and actively target nascent metastatic lesions, thus enhancing the targeted delivery efficiency. Subsequently, PDCs activated in situ by tumor cells can produce platelet microparticles (PMPs) that can actively target tumor cells by the expression of adhesion molecules such as P-selectin and thrombospondin-1 (TSP-1) and by secreting cytotoxic protein complexes mimicking cytotoxic lymphocytes. We demonstrated that the PDCs significantly suppressed lung metastasis in two tumor models, B16F10 melanomas and 4T1 breast carcinomas. Cancer metastasis is the leading cause of cancer-related deaths. The indispensable role of platelets in tumor metastasis inspires the targeted delivery strategy by using platelet-drug conjugates (PDCs). Here, we armed platelets with granzyme B and perforin nanocomplexes to suppress cancer metastasis by leveraging the natural cytotoxic mechanism of T cells. Upon systemic administration, PDCs naturally capture circulating tumor cells (CTCs) and actively target nascent metastatic lesions, thus enhancing the targeted delivery efficiency. Subsequently, PDCs activated in situ by tumor cells can produce platelet microparticles (PMPs) that can actively target tumor cells by the expression of adhesion molecules such as P-selectin and thrombospondin-1 (TSP-1) and by secreting cytotoxic protein complexes mimicking cytotoxic lymphocytes. We demonstrated that the PDCs significantly suppressed lung metastasis in two tumor models, B16F10 melanomas and 4T1 breast carcinomas.