Reverse intratumor bacteria-induced gemcitabine resistance with carbon nanozymes for enhanced tumor catalytic-chemo therapy

Emerging evidence demonstrates that intratumor bacteria promote tumor resistance to gemcitabine chemotherapy. The underlying mechanism is relate to intratumor bacteria expressing a specific cytidine deaminase (CDD) which metabolizes gemcitabine into its inactive form. Therefore, to overcome tumor resistance to gemcitabine, the CDD activity of intratumor bacteria must be restricted during chemotherapy. Herein, we developed an antitumor strategy by utilizing the dual functions of nitrogen-doped carbon nanospheres (N-CSs), i.e., as nanoinhibitors of CDD to overcome bacteria-mediated gemcitabine resistance and as nanozymes to integrate tumor catalytic therapy with chemotherapy. We found that the nitrogen-doped graphitized structure of the N-CSs could competitively bind to the active center of CDD and thus prevented gemcitabine metabolism. In addition, nitrogen doping endowed the N-CSs with peroxidase-like activity that generates •OH radicals for tumor catalytic therapy. Furthermore, in mouse cancer models with intratumor bacteria, the N-CSs successfully reversed bacterial CDD-induced gemcitabine resistance and restored tumor susceptibility to gemcitabine. The synergistic effects of catalytic therapy and chemotherapy for tumor treatment were achieved by using single N-CSs with dual nanozymatic and nanoinhibitory functions. This work provides a promising approach to overcome tumor drug-resistance induced by intratumor bacteria and synergize gemcitabine chemotherapy with nanozyme-mediated catalytic therapy for tumor treatment.