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Abstract Pyroptosis, an inflammatory cell death, has attracted great attention for potentiating a strong immune response against tumor cells. However, developing powerful pyroptosis inducers and then activating specific pyroptosis still remains challenging. Herein, a PEG‐CuP‐COF@∆St nanosystem is rationally designed, consisting of PEG‐CuP‐COF nanozyme pyroptosis inducers and tumor‐targeting bacteria of the Salmonella Typhimurium strain VNP20009 (ΔSt), with an affinity for the tumor hypoxic microenvironment. The PEG‐CuP‐COF nanozymes possessed excellent sonodynamic performance and multienzyme‐mimicking activities to generate reactive oxygen species (ROS) and then induce potent pyroptosis. The superoxide dismutase‐ and peroxidase‐mimicking activities of PEG‐CuP‐COF catalytically produced hydrogen peroxide (H2O2) and hydroxyl radicals (•OH) which have important value in triggering acute inflammatory responses and pyroptosis. Moreover, PEG‐CuP‐COF showed outstanding glutathione peroxidase‐mimicking activities, impairing the antioxidant defense in tumor cells and enhancing sonodynamic efficiency by making them more vulnerable to ROS‐induced damage. During in vivo studies, PEG‐CuP‐COF@∆St nanosystem with its self‐driven property exhibited impressive tumor‐targeting capability and activated Caspase‐3/gasdermin E‐dependent pyroptosis to inhibit tumor growth. More importantly, it induced a powerful immune memory effect to prevent bone metastasis. In summary, this study introduces an innovative approach for combinatorial sono‐catalytic immunotherapy using bacteria‐mediated tumor‐targeting delivery of nanozymes as specific pyroptosis inducers.

Abstract Intratumoral or intestinal microbiota correlates with tumorigenesis and progression, and microbiota regulation for reinforcing various anti‐tumor approaches is of significant importance, which, however, suffers from no precise regulation method and unclear underlying mechanism. Herein, a microbiome metabolism‐engineered phototherapy strategy is established, wherein Nb2C/Au nanocomposite and the corresponding phototherapy are harnessed to realize “chemical” and “physical” bacterial regulations. Flora analysis and mass spectrometry (MS) and metabonomics combined tests demonstrate that the synergistic microbiota regulations can alter the abundance, diversity of intratumoral microbiome, and disrupt metabolic pathways of microbiome and tumor microenvironment, wherein the differential singling pathways and biosynthetic necessities or metabolites that can affect tumor progression are identified. As well, anti‐TNFα is introduced to unite with bacterial regulation to synergistically mitigate bacterial‐induced inflammation, which, along with the metabolism disruptions of intratumoral microbiota and tumor microenvironment, unfreezes tumor resistance and harvests significantly‐intensified phototherapy‐based anti‐tumor outcomes against 4T1 and CT26 tumors. The clear underlying principles of microbiome‐regulated tumorigenesis and the established microbiome metabolism regulation method provide distinctive insights into tumor therapy, and can be also extended to other gut microbiome‐associated lesions interference.

Abstract MXenes, a new class of two‐dimensional (2D) nanomaterials, have shown enormous potential for biological applications. Notably, the development of 2D MXenes in nanomedicine is still in its infancy. Herein, a distinct W1.33C i‐MXene with multiple theranostic functionalities, fast biodegradation, and satisfactory biocompatibility is explored. By designing a parent bulk laminate in‐plane ordered (W2/3Y1/3)2AlC ceramic and optionally etching aluminum (Al) and yttrium (Y) elements, 2D W1.33C i‐MXene nanosheets with ordered divacancies are efficiently fabricated. Especially, theoretical simulations reveal that W1.33C i‐MXene possesses a strong predominance of near‐infrared (NIR) absorbance. The constructed ultrathin W1.33C nanosheets feature excellent photothermal‐conversion effectiveness (32.5% at NIR I and 49.3% at NIR II) with desirable biocompatibility and fast degradation in normal tissue rather than in tumor tissue. Importantly, the multimodal‐imaging properties and photothermal‐ablation performance of W1.33C‐BSA nanosheets are systematically revealed and demonstrated both in vitro and in vivo. The underlying mechanism and regulation factors for the W1.33C‐BSA nanosheets‐induced hyperthermia ablation are also revealed by transcriptome and proteome sequencing. This work offers a paradigm that i‐MXenes achieve the tailoring biomedical applications through composition and structure design on the atomic scale.