An enzyme-gated bioorthogonal catalytic nanoreactor for tumor specific prodrug activation  

作　　者：Yuheng Guo Fang Jiang Xiaohui Zhu Wen He Sijie Song Xuecen Shou Mengnan Wu Ting Wu Tingjing Huang Zhi Ye Xuyang Wang Zhitong Chen Yu He Yuhang Yao Zhaowei Chen Huanghao Yang 

机构地区：[1]New Cornerstone Science Laboratory,MOE Key Laboratory for Analytical Science of Food Safety and Biology,College of Chemistry,Fuzhou University,Fuzhou 350108,China [2]Food Inspection and Quarantine Technical Center of Shenzhen Customs District of the People's Republic of China,Shenzhen 518045,China [3]Institute of Biomedical and Health Engineering,Shenzhen Institute of Advanced Technology,Chinese Academy of Sciences,Shenzhen 518055,China [4]Department of Chemistry,University College London,London WC1H 0AJ,UK

出　　处：《Nano Research》2025年第2期557-570,共14页纳米研究(英文版)

基　　金：This work was funded by the National Key Research and Development Program of China(No.2020YFA0210800,H.H.Y.);the Major Project of Science and Technology of Fujian Province(No.2020HZ06006,H.H.Y.);the National Natural Science Foundation of China(Nos.22421002,22027805,and 22334004,H.H.Y.,Nos.22107019,and 22277011,Z.W.C.,No.22404025,Y.H.Y.);the Research project of General Administration of Customs of PRC(No.2024HK008,X.H.Z.).

摘　　要：Bioorthogonal catalysis mediated by abiotic transition metal catalysts(TMCs)is emerging as a momentum-gathering strategy for in situ generation of therapeutics.However,the unpredictable leakage and deposition of TMCs in living systems easily lead to nonspecific exposure of catalysts and concomitant off-target prodrug activation.Herein,we propose an enzyme-gated bioorthogonal catalytic nanoreactor constructed from hyaluronic acid(HA)-coated dendritic mesoporous silica nanoparticles(DMSNs),where the latter serves as a host for robustly immobilizing organometallic Ru(ll)catalysts via covalent interactions.The covalent immobilization of catalysts within the nanoscaffold effectively avoids nonspecific metal leakage under biological conditions.Importantly,the grafted HA not only acts as a"gatekeeper"preventing unintended catalyst exposure in nontargeted tissues but also acts as a ligand targeting CD44 overexpressed cancer cells.Upon receptor-mediated endocytosis into tumor cells,HA is degraded by the overexpressed hyaluronidase-1,leading to the channel opening of the nanoreactors and hence gaining the accessibility of Ru(ll)complexes to prodrugs.The therapeutic potency of this enzyme-gated nanoreactor in mediating site-specific activation of caged prodrugs was systematically demonstrated both in cellular settings and in tumor-bearing murine models.This enzyme-gated strategy enhances the efficacy of localized treatment while avoiding off-target prodrug activation,paving the way for advancing bioorthogonal catalysis for disease management in a safe and effective way.

关 键 词：bioorthogonal catalysis PRODRUGS enzyme-gated catalyst immobilization cancer therapy 

分 类 号：O64[理学—物理化学]