Ultrasound‐Assisted H ₂ Transmitter Enables Hydrogen‐Gene Therapy to Prevent Anesthesia/Surgery‐Induced Cognitive Impairment

Abstract Postoperative cognitive dysfunction (POCD) frequently occurs after surgery, resulting in extended hospitalizations, higher healthcare expenses, and potential long‐term cognitive impairment. Despite its significant impact, effective preventive and therapeutic strategies for POCD are still lacking. Neuroinflammation plays a crucial role in the pathogenesis of POCD. To address this, a H ₂ emitter is developed that employs hydrogen‐gene therapy facilitated by ultrasound, allowing for the repair of the neuroinflammatory microenvironment in a spatiotemporally controllable manner to effectively prevent anesthesia/surgery‐induced cognitive impairment. Utilizing focused ultrasound, the blood–brain barrier can be opened in a controlled manner, enabling the efficient delivery of hydrogen emitters (HPPS) carrying siRNA to the site of neuroinflammation. On one hand, the hydrogen emitter effectively generates hydrogen to eliminate excess hydroxyl radicals; on the other hand, it utilizes siRNA to target and reduce tau protein phosphorylation. This targeted hydrogen‐gene therapy strategy has been demonstrated in both mouse and rat postoperative models to significantly reduce neuroinflammation and improve postoperative spatial memory as well as object recognition. This study introduces a novel and effective strategy for preventing anesthesia/surgery‐induced cognitive impairment and offering new insights for the treatment of other neuroinflammatory diseases.