A tumor-targeted theranostic nanomedicine with strong absorption in the NIR-II biowindow for image-guided multi-gradient therapy

Abstract

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.