Ion-Exchange-Mediated Enhancement of Lactate Oxidase Delivery for Breast Tumor Imaging and Therapy.

Bioenzymes have emerged as a promising therapeutic modality for tumor treatment, which is attributed to their unique capacity to catalytically regulate the tumor microenvironment (TME). However, most bioenzymes suffer from poor thermal and chemical stability, facile inactivation, and rapid clearance during the systemic circulation. To address this challenge, we innovatively developed an ion-exchange strategy to enhance the delivery of lactate oxidase (LOX). Initially, we synthesized Mn-TCPP through the coordination of Mn3+ with TCPP, which exhibited a negligible LOX-delivering capability. Notably, partial replacement of Mn3+ ions with Tb3+ via ion exchange significantly enhanced the LOX delivery capacity, achieving a loading efficiency of 13.25%, designated as LOX-Mn(Tb)-TCPP. LOX-Mn(Tb)-TCPP leveraged the LOX-catalyzed oxidation of lactic acid (LA) to generate substrates for Fenton-like reactions. Specifically, Mn3+ mediated the depletion of glutathione (GSH) to potentiate reactive oxygen species (ROS) production while concurrently decomposing H2O2 to generate O2, thereby synergistically augmenting the efficacy of combined chemodynamic therapy (CDT) and photodynamic therapy (PDT). Furthermore, Mn2+ released during the degradation of LOX-Mn(Tb)-TCPP accumulated at the tumor site, enabling T1-weighted magnetic resonance imaging (MRI)-guided precision tumor therapy. On the basis of this ion-exchange strategy, the present work develops a novel lactate oxidase immobilization and protection system with significantly improved enzyme delivery capacity and stability, which is further exploited for effective tumor treatment.