The centerpiece of the strategy is lactate, a molecule that sits at the heart of tumor metabolism. Cancer cells favor glycolysis even in the presence of oxygen, a phenomenon known as the Warburg effect, and the resulting lactate accumulation acidifies the tumor microenvironment, fuels new blood vessel growth through HIF-1α/VEGF signaling, recruits immunosuppressive cells, and even modifies key proteins such as p53 and MRE11 through a recently discovered epigenetic process called lactylation. By targeting lactate directly, the researchers sought to undermine the tumor’s energy supply and reverse the microenvironmental features that promote resistance and malignant progression.

The vehicle for this attack is a hollow mesoporous manganese dioxide nanoparticle, or HMnO₂, whose high surface area and large pore volume allow it to carry both an enzyme and a light-sensitive drug. The enzyme, lactate oxidase or LOX, converts lactate into pyruvate and hydrogen peroxide; the manganese dioxide carrier then decomposes that hydrogen peroxide into oxygen, which in turn sustains further lactate oxidation. This closed loop, the researchers explain, is self-sustaining: the enzyme consumes lactate and oxygen, generates hydrogen peroxide, and the carrier recycles that peroxide back into the oxygen the enzyme needs. The cycle continuously drains the tumor’s metabolic fuel, simultaneously raising oxygen levels, lowering local pH, and starving cancer cells.

The catalytic cycle was verified in a series of in vitro experiments. In the presence of lactate, LOX alone generated 50.58 µM of hydrogen peroxide, but the full HILA nanoparticle produced 4.25 times more, demonstrating that the manganese carrier amplifies the enzymatic reaction by regenerating oxygen in situ. Whereas free LOX rapidly exhausted dissolved oxygen in solution, HILA’s oxygen consumption declined only gradually, confirming that the carrier compensates for the enzyme’s oxygen appetite. The nanoparticles also proved to be responsive triggers: they degraded more readily in acidic, glutathione-rich conditions characteristic of tumors, releasing their indocyanine green payload in a pH-, glutathione-, peroxide-, and heat-dependent fashion, with near-infrared irradiation further accelerating drug liberation.

That payload, indocyanine green, is an FDA-approved near-infrared dye already used for fluorescence navigation in colorectal surgery. It can simultaneously mediate photodynamic therapy by generating singlet oxygen and photothermal therapy by converting light into heat. Yet its clinical promise has been hampered by poor stability, weak tumor targeting, and the hypoxic nature of tumors, which starves photodynamic therapy of the oxygen it needs. HILA addresses all three limitations at once. The oxygen regenerated by the catalytic cycle keeps singlet oxygen production running, the photothermal effect speeds catalytic kinetics, and the released manganese ions perform a Fenton-like reaction that churns out lethal hydroxyl radicals for chemodynamic therapy.

The photothermal measurements were striking. Under 780-nanometer irradiation, HILA achieved a temperature rise of 22.80 °C, exceeding free indocyanine green, and its photothermal conversion efficiency reached 33.83 percent—competitive with black phosphorus and gold-based agents while offering the clinical advantage of biodegradable, clinically vetted components. In lactate-enriched conditions mimicking the tumor microenvironment, HILA reached an even higher terminal temperature of 42.25 °C, because the catalytic cycle’s oxygen supply prevents the hypoxia-induced self-quenching that ordinarily degrades the dye’s performance. Its singlet oxygen quantum yield was approximately 8.9 times higher than free indocyanine green.

Tumor targeting came from a hyaluronic acid coating on the nanoparticle surface, which binds the CD44 receptors abundant on colon cancer cells. Fluorescence microscopy and flow cytometry showed that pretreating cells with free hyaluronic acid to block CD44 significantly reduced uptake, confirming the mechanism. In mice bearing CT26 colon tumors, HILA accumulated progressively in tumor tissue within eight hours of injection and persisted at high levels at 24 hours, while free indocyanine green faded rapidly. Infrared thermal imaging under laser exposure showed HILA-treated tumors heating by roughly 10 °C, the strongest photothermal response among the tested formulations, and ex vivo imaging confirmed selective tumor accumulation.

The therapy’s biological punch was documented in detail. In CT26 cells, HILA depleted intracellular lactate by roughly 60 percent under irradiation and suppressed cell migration from 50.30 percent closure in controls to 19.92 percent at 24 hours. Quantifying each modality’s contribution, the researchers found that in the dark, chemodynamic therapy accounted for 59.7 percent of the killing and starvation for 40.3 percent; under laser irradiation, phototherapy dominated at 72.6 percent, with chemodynamic and starvation effects acting as adjuvants. HILA also collapsed the cells’ antioxidant defenses, cutting glutathione levels by about 75 percent and elevating oxidized glutathione, thereby unleashing a lethal storm of reactive oxygen species from combined photodynamic, photothermal, and chemodynamic sources.

In vivo results sealed the case. Mice treated intravenously with HILA followed by near-infrared irradiation showed near-complete tumor suppression, the lowest excised tumor weights, extensive apoptosis on TUNEL staining, and sharply reduced Ki67 proliferation markers. Hemolysis assays showed less than five percent hemolysis, blood biochemistry revealed no systemic toxicity fourteen days after administration, histology of major organs showed no damage, and body weights remained stable throughout treatment. Pharmacokinetic profiling showed prolonged circulation half-life and mean residence time compared with free drug, extending bioavailability and retention.

The authors describe HILA as a self-amplifying cascade in which lactate depletion, oxygen generation, acidification, glutathione consumption, and light-triggered phototherapy reinforce one another in a positive feedback loop, remodeling the tumor microenvironment while eradicating the cancer within it. By relying on biodegradable, FDA-adjacent components—an approved imaging dye, an enzyme, manganese dioxide, and hyaluronic acid—the platform offers what the researchers call a clinically translatable blueprint for minimally invasive, precision cancer therapy, one that turns the tumor’s own metabolic exhaust into the engine of its destruction.

Subject of Research: A self-sustaining lactate-depleting nanoplatform for multimodal colon cancer therapy

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

Article References: Wang, Y.-E., Zhao, S., Wu, W., Duan, Z., Li, Y., Zeng, X., Hong, L., Chen, Y., Tao, L., Zeng, K., Xiao, C., & Shen, X. (2026). Self‐Sustaining Lactate Depletion Nanoplatform Remodels Tumor Microenvironment and Augments Synergistic Photodynamic/Photothermal/Chemodynamic/Starvation Therapy for Eradication of Colon Cancer. Advanced Science, 13(53), Article e76367. https://doi.org/10.1002/advs.76367

Image Credits: AI Generated

DOI: 10.1002/advs.76367

Keywords: colon cancer, lactate oxidase, manganese dioxide nanoparticles, tumor microenvironment, photodynamic therapy, photothermal therapy, chemodynamic therapy, starvation therapy, indocyanine green, hyaluronic acid targeting, Warburg effect, nanomedicine