Cancer cells are characterized by genetic mutations that deregulate cell proliferation and suppress cell death. To arrest the uncontrolled replication of malignant cells, conventional chemotherapies systemically disrupt cell division, causing diverse and often severe side effects as a result of collateral damage to normal cells. Seeking to address this shortcoming, we pursue therapeutic regulation that is conditional, activating selectively in cancer cells. This functionality is achieved using small conditional RNAs that interact and change conformation to mechanically transduce between detection of a cancer mutation and activation of a therapeutic pathway. Here, we describe small conditional RNAs that undergo hybridization chain reactions (HCR) to induce cell death via an innate immune response if and only if a cognate mRNA cancer marker is detected within a cell. The sequences of the small conditional RNAs can be designed to accept different mRNA markers as inputs to HCR transduction, providing a programmable framework for selective killing of diverse cancer cells. In cultured human cancer cells (glioblastoma, prostate carcinoma, Ewing's sarcoma), HCR transduction mediates cell death with striking efficacy and selectivity, yielding a 20- to 100-fold reduction in population for cells containing a cognate marker, and no measurable reduction otherwise. Our results indicate that programmable mechanical transduction with small conditional RNAs represents a fundamental principle for exploring therapeutic conditional regulation in living cells.
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