Self-Sustaining Lactate Depletion Nanoplatform Remodels Tumor Microenvironment and Augments Synergistic Photodynamic/Photothermal/Chemodynamic/Starvation Therapy for Eradication of Colon Cancer.

Colon cancer remains a formidable therapeutic challenge due to its high malignancy and limited treatment options. To overcome this, we develop a multifunctional nanoplatform (HILA) using hollow mesoporous manganese dioxide (HMnO2) to co-load lactate oxidase (LOX) and the photosensitizer indocyanine green (ICG), coated with hyaluronic acid (HA) for targeted delivery to CD44-overexpressing tumor cells. Within the tumor microenvironment (TME), LOX converts lactate to more acidic pyruvate and H2O2, which subsequently react with HMnO2 to produce O2, establishing a self-sustaining HMnO2-LOX catalytic cycle that continuously depletes lactate (inducing tumor starvation) while alleviating hypoxia. The acidic pyruvate accelerates HMnO2 degradation, releasing ICG and Mn2+ ions. Under near-infrared irradiation, the generated O2 facilitates photodynamic/photothermal therapy (PDT/PTT) of ICG, while Mn2+ catalyzes H2O2 to generate hydroxyl radicals (•OH) for enhanced chemodynamic therapy (CDT). Crucially, the coordinated TME remodeling, (featuring lactate exhaustion, pH reduction, and O2/H2O2 accumulation) creates a positive feedback loop that fuels PDT/PTT/CDT/starvation therapy. This self-reinforcing cycle integrates PDT/PTT/CDT/starvation therapy, demonstrating potent tumor suppression in vivo and offering a paradigm for metabolic modulation-synergized oncotherapy.