Affiliation:
1. Department of Orthopedics The Affiliated Hospital of Xuzhou Medical University Jiangsu 221002 P. R. China
2. Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy Xuzhou Medical University Jiangsu 221002 P. R. China
3. Department of Orthopedics The Affiliated Huai'an Hospital of Xuzhou Medical University The Second People's Hospital of Huai'an Jiangsu 223002 P. R. China
Abstract
AbstractDue to the inherent low immunogenicity and immunosuppressive tumor microenvironment (TME) of malignant cancers, the clinical efficacy and application of tumor immunotherapy have been limited. Herein, a bimetallic drug‐gene co‐loading network (Cu/ZIF‐8@U‐104@siNFS1‐HA) is developed that increased the intracellular labile iron pool (LIP) and enhanced the weakly acidic TME by co‐suppressing the dual enzymatic activities of carbonic anhydrase IX (CA IX) and cysteine desulfurylase (NFS1), inducing a safe and efficient initial tumor immunogenic ferroptosis. During this process, Cu2+ is responsively released to deplete glutathione (GSH) and reduce the enzyme activity of glutathione peroxidase 4 (GPX4), achieving the co‐inhibition of the three enzymes and further inducing lipid peroxidation (LPO). Additionally, the reactive oxygen species (ROS) storm in target cells promoted the generation of large numbers of double‐stranded DNA breaks. The presence of Zn2+ substantially increased the expression of cGAS/STING, which cooperated with ferroptosis to strengthen the immunogenic cell death (ICD) response and remodel the immunosuppressive TME. In brief, Cu/ZIF‐8@U‐104@siNFS1‐HA linked ferroptosis with immunotherapy through multiple pathways, including the increase in LIP, regulation of pH, depletion of GSH/GPX4, and activation of STING, effectively inhibiting cancer growth and metastasis.
Funder
Key University Science Research Project of Jiangsu Province
Subject
Biomaterials,Biotechnology,General Materials Science,General Chemistry