Mechanically Triggered DNA Nanovehicles for Targeted Dual‐Drug Cancer Therapy

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.