Programmable DNA‐Based Synthetic Organelles as Telomerase Traps for Cell Cycle Regulation in Cancer Cells

Abstract Cancer cells exhibit aberrant cell cycle machinery, presenting a compelling target for therapeutic intervention. Telomerase, a cell cycle‐associated enzyme overexpressed in most cancer cells, represents a promising target, particularly through spatial manipulation within the cell. The study introduces a novel class of programmable synthetic organelles engineered to function as telomerase traps and block cancer cell cycle. The synthetic organelle comprises two modular DNA components: a Y‐shaped DNA scaffold and a telomerase‐actuated linear DNA device. Following cellular internalization, telomerase initiates a strand displacement reaction within the linear DNA. This reaction releases the linker DNA that subsequently drives the assembly of the Y‐shaped DNA into a dense, micron‐scale DNA microgel (synthetic organelle) that entraps telomerase. Confinement within the synthetic organelle attenuates telomerase activity, triggering cell cycle arrest in cancer cells. Molecular analysis confirms targeted dysregulation of key effectors within the Cyclin (cell cycle protein)‐Cyclin dependent kinase (CDK)‐Cyclin‐dependent kinase inhibitor (CKI) pathway, translating to suppression of cancer cell proliferation. This precise intervention further induces cytoskeletal disruption, morphological transformation, and cell migration enhancement. The findings establish a versatile DNA nanotechnology system for constructing functional synthetic organelles that spatially reprogram enzyme activity and directly modulate fundamental cellular processes. This approach underscores the significant potential of dynamic DNA assemblies in advancing next‐generation cancer therapeutics.