Precise Aβ clearance and antioxidant therapy in Alzheimer's disease via photoacoustic imaging-guided palladium hydride nanosheet-mediated photothermal treatment.

Inflammation and oxidative stress are critical pathological hallmarks of Alzheimer’s disease (AD). Hydrogen therapy shows promise due to its selective hydroxyl radical (∙OH) scavenging capacity, yet conventional hydrogen delivery fails to effectively accumulate in the brain due to low solubility and rapid diffusion. Here, we report ultra-small palladium hydride (PdH) nanosheets as a dual-functional nanomedicine for AD treatment. The PdH nanosheets exhibit high hydrogen-releasing efficiency via autocatalysis, enabling in situ ∙OH scavenging in the brain. Concurrently, their near-infrared (NIR) photothermal effect, degrading amyloid-β (Aβ) aggregates and transiently enhancing blood-brain barrier (BBB) permeability for improved drug delivery. In AD mice, intravenous PdH treatment combined with NIR irradiation significantly reduced escape latency in the Morris water maze, paralleling reductions in brain Aβ plaques and ROS levels. This study establishes a synergistic strategy of nanoscale hydrogen delivery and photothermal therapy, addressing the dual challenges of BBB penetration and multi-pathology intervention in AD.