Ultrasound‐Activated Selenium Nanocarrier: Bactericidal Enhancement and Osseointegration Promotion for Implant‐Associated Infections

Abstract Implant‐associated infections (IAIs) are common and challenging complications of orthopedic surgery. The physical barrier formed by biofilms and the antioxidant defense system of bacteria shield them from attack by antimicrobial agents and immune cells, leading to irreversible bone loss and the failure of osseointegration. To address these challenges and enhance osseointegration in the presence of biofilm infections, a sequential therapy strategy is proposed using an ultrasound‐activated nanocarrier, PLGA@H/Se, designed to disrupt bacterial defenses and subsequently enhancing osteogenic differentiation. As expected, PLGA@H/Se, when activated by ultrasound, induces a cavitation effect that disrupts the outer barrier of the biofilm, while promoting the deep delivery of encapsulated SeNPs and the antimicrobial peptide HHC‐36. The SeNPs target the internal H₂S‐based antioxidant defense in bacteria, thereby synergistically enhancing the bactericidal effect of HHC‐36. Furthermore, the sustained release of SeNPs regulates selenoprotein expression, boosts antioxidant stress responses, and activates the Wnt/β‐catenin pathway, which helps restore the osteogenic differentiation potential of BMSCs impaired by oxidative damage, both in vitro and in vivo. Collectively, this ultrasound‐based sequential system facilitates functional osseointegration under pathological conditions, offering a practical and comprehensive strategy for treating IAIs.