Ferritin‐Nanocaged Aggregation‐Induced Emission Drug Vitexin Inhibits Ferroptosis to Treat Asthenozoospermia

Abstract Asthenozoospermia, a major cause of male infertility characterized by impaired sperm motility, is critically driven by oxidative stress and dysregulated iron metabolism, which directly induce ferroptosis in sperm cells. To address this, a novel nanotheranostic platform utilizing ferritin nanocages to encapsulate vitexin, a natural flavonoid with potent antioxidant properties and unique aggregation‐induced emission (AIE) characteristics, is introduced. This ferritin nanocage‐loaded vitexin (HFn@VI) system combines the iron‐chelating capability of ferritin with vitexin's ability to mitigate oxidative stress, enabling precise dual‐targeting of the ferroptotic pathways in spermatogenic cells. In the asthenozoospermia model mice, HFn@VI significantly improves sperm count and kinematic parameters (motility, velocity) without observable systemic toxicity, demonstrating superior therapeutic efficacy. Mechanistic studies reveal that the ferritin component elevates ferritin heavy chain 1(FTH1) levels, sequestering free iron ions and reducing cellular iron overload. Concurrently, vitexin activates the nuclear factor erythroid 2‐related factor 2 (Nrf2)/heme oxygenase‐1 (HO‐1) pathway, enhancing glutathione peroxidase 4 (GPX4) expression to inhibit lipid peroxidation and ferroptosis. This study pioneers the application of vitexin, a natural product exhibiting AIE characteristics, as a therapeutic agent in reproductive medicine and underscores the potential of dual‐target nanomedicines for precise ferroptosis intervention, establishing a new paradigm for treating male infertility through advances in material science.