Mechanically Triggered DNA Nanovehicles for Targeted Dual‐Drug Cancer Therapy

ABSTRACT Stimuli‐responsive dual‐drug delivery systems enable precise therapeutic control by co‐releasing multiple agents, enhancing synergy while reducing dosage and side effects. Mechanical dysregulation is a hallmark of various diseases, yet force‐responsive platforms remain rare. Here, we introduce a DNA‐based mechanical nanovehicle that releases two anticancer drugs—TMPyP4 and doxorubicin—in response to tensile forces generated by integrin receptors at cell–cell junctions. The cholesterol‐modified DNA constructs anchor to the cell membrane and undergoes force‐induced structural changes, triggering rapid drug release under defined mechanical conditions. Our studies demonstrated selective activation in HeLa and MCF‐7 cancer cells, achieving potent cytotoxicity while minimizing off‐target effects in low‐tension HEK293T cells. This modular platform integrates mechanosensing, real‐time force visualization, and targeted therapy, establishing a new class of mechanoresponsive dual‐drug delivery systems for safer and more effective cancer treatments.