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

ABSTRACT 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 (HMnO ₂ ) 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 H ₂ O ₂ , which subsequently react with HMnO ₂ to produce O ₂ , establishing a self‐sustaining HMnO ₂ ‐LOX catalytic cycle that continuously depletes lactate (inducing tumor starvation) while alleviating hypoxia. The acidic pyruvate accelerates HMnO ₂ degradation, releasing ICG and Mn ²⁺ ions. Under near‐infrared irradiation, the generated O ₂ facilitates photodynamic/photothermal therapy (PDT/PTT) of ICG, while Mn ²⁺ catalyzes H ₂ O ₂ to generate hydroxyl radicals (•OH) for enhanced chemodynamic therapy (CDT). Crucially, the coordinated TME remodeling, (featuring lactate exhaustion, pH reduction, and O ₂ /H ₂ O ₂ 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.