Platelet-bioengineered hiPSC-sEVs achieve targeted repair of fibrotic sinoatrial node in preclinical SND models.

Abstract

Sinus node dysfunction, a prevalent arrhythmia in aging populations, is characterized by fibrosis and loss of pacemaker activity, necessitating pacemaker implantation. Current therapies fail to reverse the underlying pathology. Small extracellular vesicles derived from human induced pluripotent stem cells possess regenerative potential but lack targeted delivery. Here, we engineer platelet membrane-fused vesicles that synergistically combine collagen targeting for ischemic injury homing with immune evasion. In a rat model of sinus node dysfunction, these modified vesicles exhibit 3.1-fold higher accumulation in the sinoatrial node compared to unmodified vesicles, resulting in a 63% reduction in fibrosis and significant restoration of heart rate and intrinsic pacemaker function. The vesicles mitigate fibroblast activation and protect cardiomyocytes from oxidative stress. This study establishes a targeted, cell-free nanotherapeutic platform for resolving fibrosis and electrophysiological dysfunction in sinus node disease.