Targeted nanodelivery strategies for atrial fibrillation: concomitant targeting of fibrosis suppression and electrical conduction restoration through advanced nanobiotechnology.

Atrial fibrillation (AF), the most common form of cardiac arrhythmia, is closely associated with atrial fibrosis and electrophysiological remodeling, both of which contribute to its persistence and recurrence. Current treatment strategies remain limited in effectiveness and safety, highlighting the need for novel therapeutic approaches. Nanocarrier-mediated delivery systems represent a promising approach, enabling targeted delivery of drugs and genes to modulate fibrotic pathways and restore electrical homeostasis. The review examines the molecular mechanisms driving AF-related fibrosis, including dysregulation of the TGF-β/Smad and Wnt/β-catenin signaling cascades, as well as the influence of neuro-cardiac interactions, lipid metabolism abnormalities, and oxidative stress. We systematically evaluate nanocarriers, such as lipid nanoparticles (LNPs), polymeric systems (PLGA/PEG), and metal-based nanomaterials (AuNPs, AgNPs), to enhance cardiac targeting, prolong circulation, and mitigate off-target effects. Notably, CRISPR-Cas9-loaded nanoparticles and siRNA/mRNA delivery systems demonstrate efficacy in suppressing extracellular matrix deposition and restoring connexin 43-mediated electrical coupling. In addition, stem cell-derived extracellular vesicles (EVs) integrated with nanocarriers provide cell-free therapeutic options for myocardial repair. Key challenges, including biocompatibility, delivery precision, and long-term biosafety, are critically discussed, alongside emerging research directions involving artificial intelligence-guided nanodrug design and hybrid systems combining bioelectronic interfaces with nanoscale platforms. The integration of nanobiotechnology with molecular cardiology offers a path toward precision nanomedicine, enabling mechanism-based interventions that may transform the prevention and treatment of AF and facilitate the translation of preclinical advances into clinical application.