Cascade specific endogenous Fe^(3+)interference and in situ catalysis for tumor therapy with stemness suppression  

作　　者：Jiajie Chen Yitong Wang Jian Huang Zhibo Yang Huicong Niu Xiaolian Su Jimin Huang Hongshi Ma Yufang Zhu Chengtie Wu Jianlin Shi 

机构地区：[1]State Key Laboratory of High Performance Ceramics and Superfine Microstructure,Shanghai Institute of Ceramics,Chinese Academy of Sciences,Shanghai 200050,China [2]Center of Materials Science and Optoelectronics Engineering,University of Chinese Academy of Sciences,Beijing 100049,China [3]Department of Radiology,Shanghai Tenth People’s Hospital,School of Medicine,Tongji University,Shanghai 200072,China [4]Department of Neurology,Minhang Hospital,Fudan University,Shanghai 200032,China [5]Shanghai Frontiers Science Center of Nanocatalytic Medicine,Shanghai Tenth People’s Hospital,School of Medicine,Tongji University,Shanghai 200331,China [6]Materials Genome Institute,Shanghai University,Shanghai 200444,China

出　　处：《National Science Review》2025年第2期253-269,共17页国家科学评论(英文版)

基　　金：supported by the National Key Research and De-velopment Program of China(2022YFB3804500);the Shanghai Pilot Program for Basic Research-Chinese Academy of Sciences,Shanghai Branch(JCYJ-SHFY-2022-003);the National Natu-ral Science Foundation of China(22335006 and 32101090);the China Postdoctoral Science Foundation(2024M763409);the Shanghai Rising-Star Project(Sailing Program)(24YF2753400);the Key Research Program of Frontier Sciences,Chinese Academy of Sciences(ZDBS-LY-SLH029).

摘　　要：Cancer stem-li ke cel ls(CSCs),featuring high tumorigenicity and invasiveness,are one of the critical factors leading to the failure of clinical cancer treatment such as metastasis and recurrence.However,current strategies suffer from the low stemness-inhibiting efficacy on CSCs by conventional molecular agents and the poor lethal effects against bulk tumor cells.Here we engineer a coordination nanomedicine by 2,5-dihydroxyterephthalic acid(DHT)complexing zinc ions(Zn^(2+))as a double-effect nanodisrupter of tumor iron(Fe)and redox homeostasis for catalysis-boosted tumor therapy with stemness inhibition.Taking advantage of the much higher binding force of DHT toward Fe^(3+),this nanomedicine can specifically chelate endogenous Fe^(3+)into its nanostructure and release Zn^(2+),and the in situ formed hexacoordinated Fe-DHT conformation is of much enhanced reducibility in order to promote reactive oxygen species(ROS)production in tumors.The nanomedicine-mediated Fe depletion and ROS generation collectively induce CSC differentiation via downregulating the Wnt signaling and inducing forkhead box O3(FoxO3)activation,respectively.Notably,the combined tumor-selective ROS generation and Zn^(2+)-induced antioxidation dysfunction potently trigger intratumoral oxidative damage leading to both cellular apoptosis and ferroptosis.This nanomedicine,capable of synchronously treating CSCs and bul k tumor cel ls,has been demonstrated to effectively inhibit the growth,postoperative recurrence and metastasis of orthotopic triple-negative breast tumors in vivo,offering an encouraging candidate of cancer therapeutic agents for treating CSCs-enriched malignancy.

关 键 词：cancer stem-likecells stemness inhibition NANOMEDICINE endogenous Fe^(3+)interference catalytic therapy 

分 类 号：R73[医药卫生—肿瘤]