Biomimetic nanozymes possessing natural enzyme-mimetic activities have been extensively applied in nanocatalytic tumor therapy. However, engineering hybrid biomimetic nanozymes to achieve superior nanozyme activity remained to be an intractable challenge in hypoxic tumors. Herein, a rod-like biomimetic hybrid inorganic MnO₂-Au nanozymes are developed, where MnO₂ and ultrasmall Au nanoparticles (NPs) are successively deposited on the mesoporous silica nanorod to cooperatively improve the O₂ content and thermal sensitivity of hypoxic solid tumors guided by multi-modal imaging. Under the catalyzing of MnO₂, the intratumoral H₂O₂ is decomposed to greatly accelerate O₂ generation, which could boost the curative effect of radiation therapy (RT) and further enhance the Au-catalyzed glucose oxidation. Mutually, the Au NPs can steadily and efficiently catalyze the oxidation of glucose in harsh tumor microenvironment, thus sensitizing tumor cells to thermal ablation for mild photothermal therapy and further promoting the catalytic efficiency of MnO₂ with the self-supplied H₂O₂/H⁺. As a result, this mutual-reinforcing cycle can endow the nanoplatform with accelerated O₂ generation, thus alleviating hypoxic environment and further boosting RT effect. Furthermore, acute glucose consuming can induce downregulation expression of heat shock protein (HSP), achieving starvation-promoted mild photothermal therapy. This synthesized hybrid nanozymes proves to be a versatile theranostic agent for nanocatalytic cancer therapy.

Emerging nanozymes with natural enzyme-mimicking catalytic activities have inspired extensive research interests due to their high stability, low cost, and simple preparation, especially in the field of catalytic tumor therapy. Here, bio-breakable nanozymes based on glucose-oxidase (GOx)-loaded biomimetic Au-Ag hollow nanotriangles (Au-Ag-GOx HTNs) are designed, and they trigger an near-infrared (NIR)-II-driven plasmon-enhanced cascade catalytic reaction through regulating tumor microenvironment (TME) for highly efficient tumor therapy. Firstly, GOx can effectively trigger the generation of gluconic acid (H⁺) and hydrogen peroxide (H₂O₂), thus depleting nutrients in the tumor cells as well as modifying TME to provide conditions for subsequent peroxidase (POD)-like activity. Secondly, NIR-II induced surface plasmon resonance can induce hot electrons to enhance the catalytic activity of Au-Ag-GOx HTNs, eventually boosting the generation of hydroxyl radicals (•OH). Interestingly, the generated H₂O₂ and H⁺ can simultaneously induce the degradation of Ag nanoprisms to break the intact triangle nanostructure, thus promoting the excretion of Au-Ag-GOx HTNs to avoid the potential risks of drug metabolism. Overall, the NIR-II driven plasmon-enhanced catalytic mechanism of this bio-breakable nanozyme provides a promising approach for the development of nanozymes in tumor therapy.

Checkpoint blockade based immune therapy has shown to be effective but benefit only the minority of patients whose tumors have been pre-infiltrated by T cells. To overcome this obstacles, a PEG-modified Bi₂Se₃ nanocage (NC) loaded with imiquimod (R848), which could efficiently destroy the tumors thus producing enough tumor-associated antigens (TAA) and with the existence of R848, a toll-like-receptor-7 agonist, could generate strong anti-cancer immune responses is reported in this study. Moreover, immunogenic Bi₂Se₃ NC-PEG/R848 mediated photothermal therapy (PTT) sensitizes tumors to checkpoint inhibition mediated by a PD-L1 antibody, not only ablating cancer cells upon NIR laser but also causing strong anti-cancer immunity to suppress distant tumor growth post PTT. Both in vitro and in vivo experiments demonstrate that the Bi₂Se₃ NC-PEG/R848 could effectively activate a PTT-induced immune response as well as silence immune resistance based on PD-L1 checkpoint blockade to ablate the primary tumor and further inhibit the tumor metastasis. Bi₂Se₃ NC reported here exhibits high photothermal conversion efficiency and stability, as well as competent drug loading capacity with large hollow structures and high surface area. Our study not only provides a facial way to synthesize Bi₂Se₃ NC, but also offers an alternative strategy for tumor metastasis.