A Herbal-Piezoelectric Heterojunction Strategy to Potentiate Bacterial Cuproptosis-Like Death and Remodel the Inflammatory Microenvironment in Infection-Associated Implant Osteomyelitis.

For infection-associated implant osteomyelitis (IAOM) caused by Staphylococcus aureus, copper-induced bacterial death holds great potential. However, inducing bacterial cuproptosis-like death using low concentrations of copper (Cu) ions remains a challenge. Therefore, a "herbal-piezoelectric heterojunction" (Herbal-Piezo-HJ) is designed by integrating berberine (Ber) with Cu ion-doped Strontium titanate (SrTiO3, STO) on a Ti substrate (STO-Cu@Ber). Ber and acoustoelectric therapy (SPT) synergistically enhance the efficacy of low-concentration Cu ions in inducing bacterial cuproptosis-like death. The formation of inorganic/organic heterojunctions significantly enhances piezoelectric performance, generating marked electronic asymmetry at the interface under ultrasonic (US) irradiation and producing a large amount of reactive oxygen species (ROS). ROS and Ber together damage bacterial cell walls and membranes, promoting Cu ion uptake into bacterial cells. Consequently, the bacterial glycolytic respiratory mode is altered, the tricarboxylic acid cycle is significantly inhibited, and a large amount of nutrients are leaked, resulting in bacterial cuproptosis-like death. Additionally, Herbal-Piezo-HJ downregulates arachidonic acid metabolites, activates the cyclic adenosine monophosphate (cAMP) signaling pathway to resolve the inflammatory response after infection clearance, and promotes bone integration. Overall, the combination of herbal therapy and SPT to enhance bacterial cuproptosis-like death offers a promising strategy for eradicating IAOM.