A Tumor‐targeted Theranostic Nanomedicine with strong absorption in the NIR-II Biowindow for Imaging-Guided Multi-gradient Therapy

Developing new strategies to enhance tumor accumulation and therapeutic efficacy is of great importance in the field of tumor therapy. Herein, a peanut-like multifunctional nanomedicine (CuS-PGH NMs) based on CuS nanoparticles encapsulated in the poly(L-lysine) (PLL)/glucose oxidase (GOx)-hyaluronic acid (HA) shell is constructed via layer-by-layer (LbL) assembly, which shows good biocompatibility and effective multi-gradient therapy. On the basis of enhanced permeability and retention (EPR) effect, the CuS-PGH NMs can be significantly enhanced cellular uptake by tumor-overexpressed CD44 receptor and respond to hyaluronidase (HAase)-triggered the surface charge conversion. Once internalized into the tumor, the first exposed GOx could effectively deplete the endogenous glucose for starvation therapy, and the elevated H2O2 is 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 with regeneration of low-active Cu2+. Interestingly, the high content of H2O2 could in turn accelerate the Cu2+/Cu+ conversion to promote the Cu+-H2O2 reaction for enhanced chemodynamic therapy (CDT), therefore achieving efficient tumor growth suppression via synergistic starvation/CDT therapy. Subsequently, owing to the strong NIR-II absorption capability of CuS-PGH NMs, the effective photothermal tumor ablation of the weakened tumor cells could be realized by the precise guidance of NIR-II PAI. This multi-gradient therapeutic strategy was demonstrated to have an excellent antitumor activity with minimal nonspecific damages, which offers a new avenue to precise tumor therapy.