DNA Framework‐Enabled Three Dimensional Organization of Antiarrhythmic Drugs for Radiofrequency Catheter Ablation

Abstract Preorganizing molecular drugs within a microenvironment is crucial for the development of efficient and controllable therapeutic systems. Here, the use of tetrahedral DNA framework (TDF) is reported to preorganize antiarrhythmic drugs (herein doxorubicin, Dox) in 3D for catheter ablation, a minimally invasive treatment for fast heartbeats, aiming to address potential complications linked to collateral tissue damage and the post‐ablation atrial fibrillation (AF) recurrence resulting from incomplete ablation. Dox preorganization within TDF transforms its random distribution into a confined, regular spatial arrangement governed by DNA. This, combined with the high affinity between Dox and DNA, significantly increases local Dox concentration. The exceptional capacity of TDF for cellular internalization leads to a 5.5‐fold increase in intracellular Dox amount within cardiomyocytes, effectively promoting cellular apoptosis. In vivo investigations demonstrate that administering TDF‐Dox reduces the recurrence rate of electrical conduction after radiofrequency catheter ablation (RFCA) to 37.5%, compared with the 77.8% recurrence rate in the free Dox‐treated group. Notably, the employed Dox dosage exhibits negligible adverse effects in vivo. This study presents a promising treatment paradigm that strengthens the efficacy of catheter ablation and opens a new avenue for reconciling the paradox of ablation efficacy and collateral damage.