Bioinspired Bimetallic Ions Functionalized MOF SAzyme Nanocomposites for Synergistic Ferroptosis/Cuproptosis-Enhanced Immune Checkpoint Therapy

Abstract Immune checkpoint blockade (ICB) generates sustained responses in immunogenic cancers, but its effectiveness is limited in tumors lacking immune activity. Here, we construct a bioinspired bimetallic ions functionalized nanoscale metal-organic framework (NMOF) single-atom nanozyme (SAzyme) loaded with doxorubicin (Dox) (NMOF-Fe/Cu-Dox nanocomposite) to effectively trigger anti-tumor immune responses while addressing the immunosuppressive tumor microenvironment (TME). The NMOF-Fe/Cu-Dox nanocomposite has been demonstrated to efficiently reverse the TME by generating reactive oxygen species and oxidizing glutathione. Camouflaging NMOF-Fe/Cu-Dox nanocomposites with bioinspired cancer cell membrane (NMOF-Fe/Cu-Dox@M) enables its navigation to the tumor region through homologous targeting. The highly efficient uptaken by cancer cells selectively induced synergistic ferroptosis and cuproptosis in these cells. Furthermore, in vitro and in vivo experiments demonstrate that the ferroptosis in cancer cells can polarize tumor-associated macrophages (TAMs) towards anti-tumoral M1 phenotype and significantly diminish pro-tumoral M2 phenotype. We find that NMOF-Fe/Cu-Dox@M could induce the ferroptosis of M2 macrophages, while no effect to M1 macrophages. In addition, a significant increase of anti-tumor infiltrating CD8 + T cells, while a remarkable decrease of CD4 + regulatory T cells were observed. These findings suggested that NMOF-Fe/Cu-Dox@M could efficiently modulate TME, enhance tumoricidal immunity and elevate the therapeutic efficiency of ICB. Moreover, the combination of NMOF-Fe/Cu-Dox@M with αPD-1 effectively eradicated hepatocellular carcinoma cells in vivo , outperforming the use of either NMOF-Fe/Cu-Dox@M or αPD-1 alone. In summary, our study presents a therapeutic strategy that leverages coordinated ferroptosis and cuproptosis with therapeutic efficiency of ICB, underscoring the promise of combined chemoimmunotherapy.