A ROS-Responsive Doxorubicin-Loaded Liposomal Strategy Reduces Postablation Electrical Conduction Recovery in a CARTO-Guided Canine Right Atrial Model

Assessment of nanoplatform efficacy in reducing postablation electrical conduction recovery remains a major challenge in the development of controllable adjunctive therapies for radiofrequency catheter ablation (RFCA). Herein, we established a minimally invasive CARTO-guided canine model of right atrial postablation conduction recovery for mechanistic and pharmacodynamic evaluation. Here, a doxorubicin (DOX)-loaded and reactive oxygen species (ROS)-responsive liposome (DOX@rNP) was constructed to respond to high ROS levels, leading to the high local DOX concentration in the right atrium after ablation, which was 2.8-fold higher than that of the healthy group. Subsequently, released DOX induced apoptosis at the ablation site and modulated the Bax/Bcl-2 pathway, with associated effects on cleaved caspase-3, γ-H2AX, and fibrosis-related remodeling. CARTO-based voltage mapping and pacing assessment showed that DOX@rNP helped maintain postablation conduction block in both the short-term (30 days) and long-term (180 days). Additionally, in vivo electrocardiographic results showed that DOX@rNP treatment was associated with a lower observed electrical conduction recurrence rate than RFCA alone at 180 days (20.0% vs 80.0%), with a significant difference based on binary conduction-outcome analysis using a one-tailed Welch’s t -test. This study establishes a large-animal model of postablation electrical conduction recovery and supports a ROS-responsive liposomal strategy for reinforcing ablation-site injury and suppressing lesion reconnection.