Affiliation:
1. Department of Thoracic Surgery Shanghai Pulmonary Hospital School of Medicine Tongji University Shanghai 200433 P. R. China
2. Institute of Molecular Medicine (IMM) Shanghai Key Laboratory for Nucleic Acid Chemistry and Nanomedicine Renji Hospital School of Medicine Shanghai Jiao Tong University Shanghai 200127 P. R. China
3. Soochow Univ, Inst Funct Nano & Soft Mat FUNSOM Jiangsu Key Lab Carbon Based Funct Mat & Devices Suzhou 215123 P. R. China) # Chao Gu and Xueliang Liu contributed equally to this work.
Abstract
AbstractChemo‐dynamic therapy (CDT) based on the Fenton or Fenton‐like reaction has emerged as a promising approach for cancer treatment. However, autophagy‐mediated self‐protection mechanisms of cancer cells pose a significant challenge to the efficacy of CDT. Herein, we developed metal‐DNA nanocomplexes (DACs‐Mn) to enhance CDT via DNAzyme inhibition of autophagy. Specifically, Mn‐based catalyst in DACs‐Mn was used to generate highly hydroxyl radicals (⋅OH) that kill cancer cells, while the ATG5 DNAzyme incorporated into DACs‐Mn inhibited the expression of autophagy‐associated proteins, thereby improving the efficacy of CDT. By disrupting the self‐protective pathway of cells under severe oxidative stress, this novel approach of DACs‐Mn was found to synergistically enhance CDT in both in vitro and in vivo models, effectively amplifying tumor‐specific oxidative damage. Notably, the Metal‐DNA nanocomplexes can also induce immunogenic cell death (ICD), thereby inhibiting tumor metastasis. Specifically, in a bilateral tumor model in mice, the combined approach of CDT and autophagy inhibition followed by immune checkpoint blockade therapy shown significant potential as a novel and effective treatment modality for primary and metastatic tumors.
Funder
National Key Research and Development Program of China
National Natural Science Foundation of China
Subject
General Chemistry,Catalysis