Lysosome‐Featured Cell Aggregate‐Released Extracellular Vesicles Regulate Iron Homeostasis and Alleviate Post‐Irradiation Endothelial Ferroptosis for Mandibular Regeneration

Abstract Ferroptosis, a form of regulated cell death driven by iron accumulation and lipid peroxidation, is implicated in various diseases, but effective therapeutic strategies remain limited. Lysosomal impairments cause iron dysregulation and initiate ferroptosis, which potentially contribute to ionizing radiation‐induced tissue damages. Here, the role of intercellular lysosomal regulation in governing iron homeostasis and protecting against ferroptosis is investigated in models of stem cell aggregation and mandibular regeneration post‐irradiation. Lysosomes are discovered to accumulate in specific regions within multi‐stem cell aggregates and regulate cell aggregate formation based on iron control, which is occurred through hypoxic signaling‐driven lysosomal redistribution mediated by extracellular vesicles. These vesicles exhibit lysosomal features and possess iron‐regulating properties, which rescue lysosomal defects to restore iron homeostasis and mitigate ferroptosis in recipient endothelial cells against the irradiation challenge. Based on lysosomal regulation and anti‐ferroptosis, these cell aggregate‐released extracellular vesicles (CA‐EVs) stimulate the growth of CD31 + endomucin + specialized vessels despite irradiation both in vitro and in vivo, which further promote bone regeneration of post‐irradiation mandibular defect. These findings highlight the potential of taking CA‐EVs as natural therapeutic agents to safeguard lysosomal function, modulate iron metabolism, and protect against ferroptosis, paving an avenue for combating post‐irradiation endothelial injuries and enhancing tissue regeneration.