Molybdenum oxide (MoOx) nanosheets have drawn increasing attention for minimally invasive cancer treatments but still face great challenges, including complex modifications and the lack of efficient accumulation in tumor. In this work, a novel multifunctional degradable FA-BSA-PEG/MoOx nanosheet was fabricated (LA-PEG and FA-BSA dual modified MoOx): the synergistic effect of PEG and BSA endows the nanosheet with excellent stability and compatibility; the FA, a targeting ligand, facilitates the accumulation of nanosheets in the tumor. In addition, DTX, a model drug for breast cancer treatment, was loaded (76.49%, 1.5 times the carrier weight) in the nanosheets for in vitro and in vivo antitumor evaluation. The results revealed that the FA-BSA-PEG/MoOx@DTX nanosheets combined photothermal and chemotherapy could not only inhibit the primary tumor growth but also suppress the distant tumor growth (inhibition rate: 51.7%) and lung metastasis (inhibition rate: 93.6%), which is far more effective compared to the commercial Taxotere®. Exploration of the molecular mechanism showed that in vivo immune response induced an increase in positive immune responders, suppressed negative immune suppressors, and established an inflammatory tumor immune environment, which co-contributes towards effective suppression of tumor and lung metastasis. Our experiments demonstrated that this novel multifunctional nanosheet is a promising platform for combined chemo-photothermal therapy.Graphical Abstract
The colon tumor microenvironment has a high concentration of H 2 S and glutathione, which is highly immunosuppressive and adverse to multiple therapeutic methodologies such as ferroptosis. Here, an engineered microbial nanohybrid based on Escherichia coli ( E. coli ) and Cu 2 O nanoparticles to specific colon tumor therapy and immunosuppression reversion is reported. The as-prepared E. coli @Cu 2 O hybrid can accumulate in tumor sites upon intravenous injection, and Cu 2 O nanoparticles convert to Cu x S by consuming the endogenous H 2 S, which exhibits strong photothermal conversion at near-infrared II (NIR II) biological window. Furthermore, E. coli @Cu 2 O is able to induce cellular ferroptosis and cuproptosis through inactivation of glutathione peroxidase 4 and aggregation of dihydrolipoamide S-acetyltransferase, respectively. Photothermal-enhanced ferroptosis/cuproptosis achieved by E. coli @Cu 2 O reverses the immunosuppression of colon tumors by triggering dendritic cell maturation (about 30%) and T cell activation (about 50% CD8 + T cells). Concerted with immune checkpoint blockade, the engineered microbial nanohybrid can inhibit the growth of abscopal tumors upon NIR illumination. Overall, the designed microbial nanohybrid can achieve tumor-specific photothermal-enhanced ferroptosis/cuproptosis and immunosuppression reversion, showing promise in precise tumor therapy in future clinical translation.
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