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Qian, Ruo‐Can; Zhou, Ze‐Rui; Wu, Yuting; Yang, Zhenglin; Guo, Weijie; Li, Da‐Wei; Lu, Yi
Angewandte Chemie, December 5, 2022, Volume: 61, Issue: 49Journal Article
Despite the promise of combination cancer therapy, it remains challenging to develop targeted strategies that are nontoxic to normal cells. Here we report a combination therapeutic strategy based on engineered DNAzyme molecular machines that can promote cancer apoptosis via dynamic inter‐ and intracellular regulation. To achieve external regulation of T‐cell/cancer cell interactions, we designed a DNAzyme‐based molecular machine with an aptamer and an i‐motif, as the MUC‐1‐selective aptamer allows the specific recognition of cancer cells. The i‐motif is folded under the tumor acidic microenvironment, shortening the intercellular distance. As a result, T‐cells are released by metal ion activated DNAzyme cleavage. To achieve internal regulation of mitochondria, we delivered another DNAzyme‐based molecular machine with mitochondria‐targeted peptides into cancer cells to induce mitochondria aggregation. Our strategy achieved an enhanced killing effect in zinc deficient cancer cells. A combination therapeutic strategy based on engineered DNAzyme molecular machines was designed for promoting cancer apoptosis via dynamic inter‐ and intracellular regulation. Our strategy resulted in an enhanced killing effect, demonstrated using zinc deficient cancer cells, thus providing a promising next‐generation combination therapy for cancer.
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