Targeting fibrotic regions for in situ cardiac regeneration

Background Myocardial infarction leads to irreversible loss of cardiomyocytes and maladaptive fibrotic scarring. Converting resident fibroblasts into functional cardiomyocytes offers a promising therapeutic avenue but is limited by the absence of delivery systems that can achieve precise spatial targeting within the dynamically beating heart. Purpose This study aimed to develop and evaluate an integrated soft bioelectronic interface capable of performing real-time high-resolution electrophysiological mapping and spatially confined directional gene delivery to achieve targeted in situ cellular reprogramming and functional repair of infarcted myocardium. Methods A soft, stretchable epicardial electrode array was fabricated based on advanced compliant materials. In a murine myocardial infarction model, the platform was utilized to: 1) identify and characterize fibrotic regions through real-time, high-density electrophysiological mapping; 2) deliver defined reprogramming factor combinations via directional electroporation specifically to the mapped pathological zones; 3) serially evaluate post-intervention electrical and mechanical function. In vivo cell fate conversion was assessed using a genetic reporter model. Outcomes were analyzed by histology, molecular assays, functional imaging, and electrophysiological recordings. Results The bioelectronic interface successfully quantified post-infarct fibrotic substrates, showing a ~50% reduction in local field amplitude (18.59±5.296 mV to 9.526±4.854 mV, P<0.001). Directional electroporation achieved heart-restricted delivery, with cardiac fluorescence 18-fold higher than scrambled controls (P<0.001) and no off-target organ expression. Lineage tracing confirmed in vivo fibroblast-to-cardiomyocyte conversion. By day 14, induced cardiomyocytes (iCMs) constituted 8.96±2.11% (miRNA) and 9.03±1.93% (mRNA) of the total cardiomyocyte area, with conversion efficiencies >40%. These iCMs exhibited sarcomeric assembly and connexin-43⁺ gap junctions. In situ cardiac reprogramming restored electrical function as near-field potentials recovered from 6.81±3.24 mV (MI control) to 12.10±4.42 mV (miRNA combo, P<0.01). Echocardiography demonstrated sustained functional recovery over 16 weeks, with scar burden reduced by 78% (collagen volume: 13.05±2.88% to 2.81±0.95%, P<0.001). Comprehensive biosafety assessment revealed no ectopic reprogramming or systemic toxicity. Conclusion This study presents a closed-loop bioelectronic strategy that synergizes real-time pathological mapping with spatially precise therapeutic delivery to enable effective in situ cardiac regeneration. This integrated approach achieves significant structural and functional repair after myocardial infarction, establishing a novel translational framework for targeted regenerative therapy.