Developing new strategies to enhance drug accumulation in the tumor and therapeutic efficacy is of great importance in the field of tumor therapy. Herein, a peanut-like multifunctional nanomedicine (CuS-PGH NMs) made of CuS nanoparticles encapsulated in poly(l-lysine)(PLL)/glucose oxidase (GOx)-hyaluronic acid (HA) shells has been constructed via layer-by-layer (LbL) assembly, and shows good biocompatibility and effective multi-gradient therapy. Because of the enhanced permeability and retention (EPR) effect, the CuS-PGH NMs could significantly enhance the cellular uptake by tumors overexpressing CD44 receptors, which respond to hyaluronidase (HAase)-triggered surface charge conversion. Once internalized by the tumor, GOx was the first to be exposed and could effectively deplete endogenous glucose for starvation therapy, and the excess H2O2 was then converted into highly toxic hydroxyl radicals (˙OH) via a Cu+-mediated Fenton-like reaction for chemodynamic therapy (CDT). Meanwhile, the as-obtained Cu+ ions accompanied the regenerated less-active Cu2+ ions. Interestingly, the high content of H2O2 could, in turn, accelerate Cu2+/Cu+ conversion to promote the Cu+-H2O2 reaction for enhanced chemodynamic therapy (CDT), thereby achieving efficient tumor growth suppression via synergistic starvation/CDT therapy. Subsequently, owing to the strong NIR-II absorption capability of CuS-PGH NMs, effective photothermal tumor ablation of the weakened tumor cells could be realized with the precise guidance of NIR-II PAI. This multi-gradient therapeutic strategy has been demonstrated to have excellent antitumor activity with minimal nonspecific damages, and offers a new avenue to precise tumor therapy.

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