A pH/miR-21 dual-responsive multifunctional DNA tetrahedron for targeted tumor imaging and synergistic chemo-gene therapy

Small interfering RNA (siRNA) presents promising prospects as a therapeutic agent; its clinical application is constrained by challenges such as inefficient delivery and off-target effects. This study developed a multifunctional DNA Tetrahedron (MDT) platform for synergistic delivery of siRNA and the chemotherapeutic agent doxorubicin (DOX) to optimize delivery efficiency and enhance therapeutic efficacy. The MDT structure incorporates aptamers for targeted cell recognition and modifies the DNA hairpins responsive to the tumor biomarker microRNA-21 (miR-21). The MDT provides degradation protection for siRNA and enables specific delivery to tumor cells. Following cellular internalization, the MDT responds to the acidic environment of lysosomes; its pH-responsive i-motif structure undergoes assembly by protonation, simultaneously reducing lysosomal acidity and inhibiting hydrolase activity, thereby facilitating protective release of siRNA. The DNA hairpins incorporated with the MDT transform structurally in response to miR-21 within tumor cells, generating a fluorescent signal and releasing DOX, thereby detecting tumor cells and initiating chemotherapy. Experimental results demonstrate that synergistic delivery of siRNA and DOX via this MDT platform significantly enhances tumor cell elimination. This study provides a universal strategy for developing intelligent therapeutic carriers; by replacing the aptamer and siRNA, the system can be customized for specific targeting and elimination of different tumor cell types.