Biomimetic metal organic frameworks mediated by metformin and 1-MT for enhancing the synergistic treatment of photodynamic therapy, photothermal therapy and immunotherapy

Design of novel nanoreactor that integrates multiple therapeutic for tumor remains to be challenging. Here, we developed a multiple antitumor nanoreactor, which consisted of biomimetic Metal Organic Framework (Zn/CoMOF), metformin, cisplatin, indocyanine Green (ICG), 1-methyl-tryptophan (1-MT) and glucose oxidase (GOD) payload, Mxene and AS1411-aptamer decoration. The constructed Nb2C/aptamer-PDA/GOD@Zn/Co-MOF@M/ C (NMC) targeted to the tumor cells via AS1411-aptamer, and magnetic Nb2C/aptamer-PDA/ICG@Zn/CoMOF@1-MT/C (NTC) targeted to the tumor cells via AS1411-aptamer and magnetic effect. In the acidic tumor microenvironment, NMC can consume endogenous glucose to generate the H2O2 and gluconic acid by GODmediated reaction and "starved" the tumors. The abundant of H2O2 is catalyzed to generate the oxygen by the Co and singlet oxygen (1O2) by the ICG, which can improved the hypoxic environment of the tumor and effectively reduced the resistance to PDT. The metformin both can block the glycolytic reaction, causing cell apoptosis and reverse tumor immunosuppression through endoplasmic reticulum related PD-L1 degradation to increase immune response. Simultaneously, metformin can hamper O2 consumption and raise the oxygen content of the tumor site to enhance the catalytic efficiency of GOD. The released 1-MT collaborates with metformin can further enhance immune response to produce apparent cytotoxic T cells. Under laser irradiation, the temperature at the tumor site increases sharply and photo-thermal effect can be generated by the Nb2C and ICG, which can lead to the tumor cell apoptosis, achieving significant photo-thermal therapeutic (PTT) effects. The Nb2C can penetrate into the deep tumor tissue due to its small size. The data revealed that joint use of NMC and NTC can trigger immune response, including the enhancement of CD8+ T cells and CD4+ T cells, the production of INF-gamma and TNF-alpha.