Triple-Combination Nanoregulator Based on Dual Energy Inhibition Strategy Induction Reshape Tumor Microenvironment for Amplified Starvation/Gas/Photothermal Therapy

Photothermal therapy (PTT) in combination with other treatment modalities is a promising cancer management strategy. However, the high expression of heat shock proteins in tumor cells limits therapeutic efficacy. Herein, a tumor microenvironment (TME) remodeling nanoregulator (MCGH) was emerged, which featured manganese carbonyl (MnCO) loaded within hollow mesoporous copper sulfide (HCuS), with hyaluronic acid (HA) and glucose oxidase (GOD) strategically gated on the HCuS surface for smart drug release and TME modulation. GOD induces starvation therapy by catalyzing the production of gluconic acid and H 2 O 2 from glucose, while H 2 O 2 accelerates MnCO breakdown, releasing large amounts of CO to trigger mitochondrial dysfunction for gas therapy. Additionally, mitochondrial dysfunction and starvation therapy synergistically decrease ATP content, subsequently down-regulating HSP90 expression and enhancing the PTT effect of HCuS. In vivo and in vitro studies demonstrated that MCGH exhibited exceptional tumor-killing efficiency, showcasing its potential as a combined starvation, gas, and photothermal tactic for tumor treatment.