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.