Mesenchymal Stem Cell‐Derived Extracellular Vesicles Ameliorate NaIO3‐Induced Dry AMD by Delivering miR‐486‐3p to Inhibit Lipocalin‐2‐Mediated Ferroptosis

ABSTRACT Dry age‐related macular degeneration (AMD), affecting over 196 million people globally, represents the leading cause of irreversible blindness with limited disease‐modifying therapies. The disease is characterized by progressive retinal pigment epithelium (RPE) degeneration driven by ferroptosis, an iron‐dependent form of regulated cell death. While mesenchymal stem cell (MSC)‐derived extracellular vesicles (EVs) show therapeutic promise, their mechanisms in counteracting RPE ferroptosis remain unexplored. Here, we prove that human umbilical cord MSC‐derived EVs (hucMSC‐EVs) significantly attenuate NaIO3‐induced retinal degeneration, preserving retinal structure and improving visual function in mice. Transcriptomic profiling identified Lipocalin‐2 (Lcn2) as a key ferroptosis‐related target. MSC‐EVs administration markedly downregulated Lcn2 and upregulated Gpx4 in NaIO3‐induced models, demonstrating potent ferroptosis suppression. Furthermore, AAV‐mediated Lcn2 overexpression induced AMD‐like retinal pathology, which was effectively attenuated by subsequent MSC‐EVs treatment. Small RNA sequencing reveals miR‐486‐3p as the key factor in the MSC‐EVs, and dual‐luciferase reporter assays confirm its direct binding to the Lcn2 3'UTR. Functional validation demonstrates that miR‐486‐3p agomir recapitulates the effects of MSC‐EVs, including preservation of retinal structure and improvement of electrophysiological responses. Our findings establish a novel strategy where hucMSC‐EVs deliver miR‐486‐3p to suppress Lcn2‐mediated ferroptosis, offering a potential treatment for dry AMD.