Nanozymes as artificial enzymes that mimicked natural enzyme-like activities have received great attention in cancer diagnosis and therapy. Biomimetic nanozymes require more consideration regarding complicated tumor microenvironments to mimic biological enzymes, thus achieving superior nanozyme activity in vivo. Here we report a biomimetic hybrid nanozyme (named rMGB) which integrates natural enzyme glucose oxidase (GOx) with nanozyme manganese dioxide (MnO 2 ) by mutual promotion for maximizing the enzymatic activity of MnO 2 and GOx. Under hypoxia environment, we observed that MnO 2 could react with endogenous H 2 O 2 to produce O 2 for enhancing the catalytic efficiency of GOx for starvation therapy. Meanwhile, we confirmed that glucose oxidation generated gluconic acid and further improved the catalytic efficiency of MnO 2 subsequently. The biochemical reaction cycle, consisting of MnO 2 , O 2 , GOx, and H + , was triggered by the tumor microenvironment and accelerated each other so as to achieve self-supplied H + and accelerate O 2 generation, enhancing the starvation therapy, alleviating tumor hypoxia and accelerating the reactive oxygen species generation in photodynamic therapy. This biomimetic hybrid nanozyme would further facilitate the development of biological nanozymes for cancer treatment.

Combination of photothermal and photodynamic therapy (PTT/PDT) offer unique advantages over PDT alone. However, to achieve synergetic PDT/PTT effect, one generally needs two lasers with different wavelengths. Near-infrared dye IR-780 could be used as photosensitizer both for PTT and PDT, but its lipophilicity limits its practical use and in vivo efficiency. Herein, a simple multifunctional IR780-loaded nanoplatform based on transferrin was developed for targeted imaging and phototherapy of cancer compatible with a single-NIR-laser irradiation. The self-assembled transferrin-IR780 nanoparticles (Tf-IR780 NPs) exhibited narrow size distribution, good photo-stability, and encouraging photothermal performance with enhanced generation of ROS under laser irradiation. Following intravenous injection, Tf-IR780 NPs had a high tumor-to-background ratio in CT26 tumor-bearing mice. Treatment with Tf-IR780 NPs resulted in significant tumor suppression. Overall, the Tf-IR780 NPs show notable targeting and theranostic potential in cancer therapy.

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The high redox level of tumor microenvironment inhibits the oxidation treatment and the immune response. Here, we innovatively develop maleimide liposome (ML) adjuvants to promote immunogenic cell death (ICD) induction and dendritic cells (DCs) maturation by glutathione (GSH) depletion for augmenting the photothermal immunotherapy of breast cancer. The ML effectively depletes the intracellular GSH and up-regulates reactive oxygen species (ROS) in both tumor cells and DCs. In tumor cells, the ROS boosted the ABTS·+ production to activate photothermal-induced ICD. In DCs, it relieved the immunosuppression, promoting DC maturation (57%) and antigen presenting. As a result of the ML assistant, the therapeutic systems improved the infiltration of CD8+ T cells to 53% in tumor tissues, eliciting strong abscopal effect and antimetastasis effect. The MLs were believed to be a superior candidate of adjuvants for enhancing immune response and cancer therapeutic efficacy.

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Anti–programmed cell death 1 ligand 1 (PD-L1) therapy is extraordinarily effective in select patients with cancer. However, insufficient lymphocytic infiltration, weak T cell–induced inflammation, and immunosuppressive cell accumulation in the tumor microenvironment (TME) may greatly diminish the efficacy. Here, we report development of the FX@HP nanocomplex composed of fluorinated polymerized CXCR4 antagonism (FX) and paclitaxel-loaded human serum albumin (HP) for pulmonary delivery of anti–PD-L1 small interfering RNA (siPD-L1) to treat orthotopic lung tumors. FX@HP induced T cell infiltration, increased expression of calreticulin on tumor cells, and reduced the myeloid-derived suppressor cells/regulatory T cells in the TME, thereby acting synergistically with siPD-L1 for effective immunotherapy. Our work suggests that the CXCR4-inhibiting nanocomplex decreases tumor fibrosis, facilitates T cell infiltration and relieves immunosuppression to modulate the immune process to improve the objective response rate of anti–PD-L1 immunotherapy.

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