Cytosolic delivery of exogenous cytochrome c (CytC) can trigger apoptosis of tumor cells, which could become a promising protein-based antitumor drug. However, current strategies for protein delivery rely on the internalization through endocytosis, and the internalized proteins can hardly escape from endosome/lysosome to exert functions in cytosol. Here, we report the design and synthesis of TG6-CytC conjugate (conjugating a tetra-guanidine small molecule (TG6) to CytC), which is directly delivered into the cytosol, triggers the release of endogenous CytC from mitochondria, and induces apoptosis of several tumor cell lines, with EC50 values down to 2.4 nM. The EC50 of TG6-CytC is ~ 3 order of magnitude lower than other reported CytC delivery platforms (EC50 ~ 1 uM). Furthermore, the TG6-CytC-induced apoptosis can be blocked by the caspase-3 inhibitor Ac-DEVD-CHO, indicating that the apoptosis is caspase-3 dependent, which is further supported by the increased level of cleaved caspase-3 after TG6-CytC treatment. This study offers a novel strategy for more efficient protein delivery that bypass the low-efficient endosome/lysosome pathway.

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