A ROS-responsive “one-two punch” nanozyme for self-supplying oxygen and suppressing immune rejection in heart transplantation

Heart transplantation offers the only life-saving option for patients with terminal heart failure; yet, the sequential "innate-adaptive" avalanche initiated by ischemia-reperfusion injury (IRI) remains the Achilles' heel of long-term graft acceptance. Current regimens overwhelmingly focus on either the adaptive or the IRI-triggered innate arm, failing to interrupt the positive-feedback loop that amplifies allo-rejection. To address this unmet need, we herein present a single ROS-responsive nanoplatform that weds dual immunosuppression with on-demand oxygenation Fe 3 O 4 @CaO 2 @Tac@HA. The core-shell Fe 3 O 4 @CaO 2 carrier simultaneously loads hyaluronic acid (HA), which is a potent dampener of innate inflammatory signaling, and tacrolimus (Tac), which is a calcineurin inhibitor that arrests adaptive T-cell activation. Upon exposure to the ROS-rich milieu of the reperfused graft, CaO 2 undergoes conversion to O 2 , promptly relieving tissue hypoxia while reducing oxidative stress. In vitro , the nanocomposite exhibits rapid ROS scavenging, sustained oxygen release and inhibit T cell activation; in vivo, it markedly prolongs cardiac-allograft survival by synchronously suppressing innate immune cells infiltration and CD8 + T-cell cytotoxicity. Collectively, Fe 3 O 4 @CaO 2 @Tac@HA offers a translatable "one-two punch" strategy that unites innate and adaptive immunomodulation, setting the stage for precision nanotherapy in cardiac transplantation.