Dynamic Simulation Assists Insights into the Deafness Prevention of a Self-Assembly Pd Nanozyme with Intrinsic Targeting

With aging increases the possibility of body impairment, deafness prevention remains a major unmet clinical challenge, largely due to the lack of effective therapeutics capable of targeting cochlear hair cells (HCs) across the blood–labyrinth barrier (BLB). Here, we report a precisely structured palladium-polyoxometalate coordinated antioxidant nanoagent (Pd single-atom nanozyme, Pd SAN), which demonstrates superior antioxidative enzyme-like capacity and robust biosafety. With identical Pd1–O4 coordinating sites and controllable size, Pd SAN effectively penetrates the BLB, accumulates within the cochlea, and protects HCs from neomycin-induced damage. Mechanistically, Pd SAN inhibits ferroptosis by preserving glutathione redox balance, reducing lipid peroxidation, stabilizing lysosomal membranes, and maintaining Fe2+ homeostasis. Notably, dynamic simulation demonstrates that Pd SAN shows comparable binding affinity to critical HC proteins (Prestin, Myo7a) as superoxide dismutase (SOD), and functionally suppresses neomycin-induced ferroptosis with equal or greater efficacy. In vivo experiments confirm that Pd SAN prevents auditory threshold shifts and mitigates cochlear structural injury, underscoring its translational potential. This study not only reveals that lysosomal damage–iron metabolism dysregulation–oxidative stress is a key axis driving aminoglycoside ototoxicity, but also establishes Pd SAN whose structure can be accurately deciphered with mass spectroscopy as an innovatively designed cochlea-targeting antioxidant nanomaterial with strong potential for clinical translation in deafness prevention.