Mitochondria-Targeted Multifunctional Nanoparticles Combine Cuproptosis and Programmed Cell Death-1 Downregulation for Cancer Immunotherapy

The combination of Cuproptosis and immune checkpoint inhibition has shown promise in treating malignant Tumors. However, it remains a challenge to deliver copper ions and immune checkpoint inhibitors efficiently and simultaneously to Tumors. Herein, a mitochondria-targeted nanoscale coordination polymer particle, Cu/TI, comprising Cu(II), and a triphenylphosphonium conjugate of 5-carboxy-8-hydroxyquinoline (TI), for effective Cuproptosis induction and programmed cell death-1 (PD-L1) downregulation is reported. Upon systemic administration, Cu/TI efficiently accumulates in tumor tissues to induce immunogenic Cancer cell death and reduce PD-L1 expression. Consequently, Cu/TI promotes the intratumoral infiltration and activation of cytotoxic T lymphocytes to greatly inhibit tumor progression of colorectal carcinoma and Triple-Negative Breast Cancer in mouse models without causing obvious side effects.