Organelle-inspired supramolecular nanomedicine to precisely abolish liver tumor growth and metastasis  

作　　者：Jie Zhan Yuhan Wang Shaodan Ma Qin Qin Ling Wang Yanbin Cai Zhimou Yang 

机构地区：[1]Shunde Hospital,Southern Medical University,The First People’s Hospital of Shunde,Foshan,528300,China [2]Guangdong Provincial Key Laboratory of New Drug Screening,School of Pharmaceutical Sciences,Southern Medical University,Guangzhou,510515,China [3]Guangdong Provincial Key Laboratory of Construction and Detection in Tissue Engineering,Southern Medical University,Guangzhou,510515,China [4]State Key Laboratory of Medicinal Chemical Biology,College of Life Sciences,Key Laboratory of Bioactive Materials,Ministry of Education,Collaborative Innovation Center of Chemical Science and Engineering,And National Institute of Functional Materials,Nankai University,Tianjin,300071,China [5]Guangdong Provincial Biomedical Engineering Technology Research Center for Cardiovascular Disease,Department of Cardiology and Laboratory of Heart Center,Zhujiang Hospital,Southern Medical University,Guangzhou,510280,China

出　　处：《Bioactive Materials》2022年第3期120-133,共14页生物活性材料（英文）

基　　金：We thank Prof.Chihua Fang from Zhujiang hospital of Southern Medical University for sharing the HepG2-luci cells and the c(RGDfC)peptide.We acknowledge the financial support from the National Science Fund for Distinguished Young Scholars(31825012);National Natural Science Foundation of China(21875116,31961143004,81921004,31900952,51973090);Tianjin Science Fund for Distinguished Young Scholars(17JCJQJC44900);Guangdong Basic and Applied Basic Research Foundation(2018A030313446,2019A1515011706,2019A1515110638);and the China Postdoctoral Science Foundation(BX20190149,2019M662972).

摘　　要：Organelles are responsible for the efficient storage and transport of substances in living systems.A myriad of extracellular vesicles(EVs)acts as a bridge to exchange signaling molecules in cell-cell communication,and the highly dynamic tubulins and actins contribute to efficient intracellular substance transport.The inexhaustible cues of natural cargo delivery by organelles inspire researchers to explore the construction of biomimetic architectures for“smart”delivery carriers.Herein,we report a 10-hydroxycamptothecin(HCPT)-peptide conjugate HpYss that simulates the artificial EV-to-filament transformation process for precise liver cancer therapy.Under the sequential stimulus of extracellular alkaline phosphatase(ALP)and intracellular glutathione(GSH),HpYss proceeds via tandem self-assembly with a morphological transformation from nanoparticles to nanofibers.The experimental phase diagram elucidates the influence of ALP and GSH contents on the self-assembled nanostructures.In addition,the dynamic transformation of organelle-mimetic architectures that are formed by HpYss in HepG2 cells enables the efficient delivery of the anticancer drug HCPT to the nucleus,and the size-shape change from extracellular nanoparticles(50-100 nm)to intracellular nanofibers(4-9 nm)is verified to be of key importance for nuclear delivery.Nuclear targeting of HpYss amplifies apoptosis,thus significantly enhancing the inhibitory effect of HCPT(>10-fold)to HepG2 cells.Benefitting from the spatiotemporally controlled nanostructures,HpYss exhibited deep penetration,enhanced accumulation,and long-term retention in multicellular spheroid and xenograft models,potently abolishing liver tumor growth and preventing lung metastasis.We envision that our organelle-mimicking delivery strategy provides a novel paradigm for designing nanomedicine to cancer therapy.

关 键 词：SELF-ASSEMBLY Organelle-mimicking Nuclear delivery Dynamic cascade process Cancer therapy 

分 类 号：R730.5[医药卫生—肿瘤] TB383[医药卫生—临床医学]