Magnetically Labelled iPSC‐Derived Extracellular Vesicles Enable MRI/MPI‐Guided Regenerative Therapy for Myocardial Infarction

ABSTRACT Stem cell‐derived extracellular vesicles (EVs) offer a promising cell‐free approach for cardiovascular regenerative medicine. In this study, we developed magnetically labelled induced pluripotent stem cell‐derived EVs (magneto‐iPSC‐EVs) encapsulated with superparamagnetic iron oxide (SPIO) nanoparticles for image‐guided regenerative treatment of myocardial infarction, in which EVs that can be detected by both magnetic resonance imaging (MRI) and magnetic particle imaging (MPI). iPSC‐EVs were isolated, characterized per MISEV2023 guidelines, and loaded with SuperSPIO20 nanoparticles using optimized electroporation conditions (300 V, 2 × 10 ms pulses), achieving a high loading efficiency of 1.77 ng Fe/10 6 EVs. In vitro results show that magneto‐iPSC‐EVs can be sensitively detected by MPI and MRI, with a detectability of approximately 10 7 EVs. In a mouse myocardial ischemia‐reperfusion model, intramyocardially injected magneto‐iPSC‐EVs (2 × 10 9 ) were imaged non‐invasively by in vivo MPI for 7 days and ex vivo MRI, with the presence of magneto‐iPSC‐EVs confirmed by Prussian blue staining. Therapeutically, both native and magneto‐ iPSC‐EVs significantly improved cardiac function, with a 37.3% increase in left ventricular ejection fraction and 61.0% reduction in scar size. This study highlights the potential of magneto‐iPSC‐EVs as a cell‐free approach for cardiovascular regenerative medicine, offering both non‐invasive imaging capabilities and therapeutic benefits for myocardial repair.