Inducing mitochondriopathy-like damages by transformable nucleopeptide nanoparticles for targeted therapy of bladder cancer  

作　　者：Da-Yong Hou Ni-Yuan Zhang Lu Wang Mei-Yu Lv Xiang-Peng Li Peng Zhang Yue-Ze Wang Lei Shen Xiu-Hai Wu Bo Fu Peng-Yu Guo Zi-Qi Wang Dong-Bing Cheng Hao Wang Wanhai Xu 

机构地区：[1]NHC and CAMS Key Laboratory of Molecular Probe and Targeted Theranostics,Heilongjiang Key Laboratory of Scientific Research in Urology,Harbin Medical University,Harbin 150001,China [2]Department of Urology,Harbin Medical University Cancer Hospital,Harbin 150001,China [3]CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety,CAS Center for Excellence in Nanoscience,National Center for Nanoscience and Technology(NCNST),Beijing 100190,China [4]School of Chemistry,Chemical Engineering&Life Science,Hubei Key Laboratory of Nanomedicine for Neurodegenerative Diseases,Wuhan University of Technology,Wuhan 430070,China

出　　处：《National Science Review》2024年第4期210-221,共12页国家科学评论（英文版）

基　　金：This work was supported by the National Key R&D Program of China(2021YFB3801000);the Regional Key Project of National Natural Science Foundation of China(U20A20385);the Overseas High-end Talents Introduction Program(G2022011023L);the National Natural Science Foundation of China(82302266,82171999 and 82002688);the Heilongjiang Province Key Research and Development Program(2022XJ03C07).

摘　　要：Mitochondriopathy inspired adenosine triphosphate(ATP)depletions have been recognized as a powerful way for controlling tumor growth.Nevertheless,selective sequestration or exhaustion of ATP under complex biological environments remains a prodigious challenge.Harnessing the advantages of in vivo self-assembled nanomaterials,we designed an Intracellular ATP Sequestration(IAS)system to specifically construct nanofibrous nanostructures on the surface of tumor nuclei with exposed ATP binding sites,leading to highly efficient suppression of bladder cancer by induction of mitochondriopathy-like damages.Briefly,the reported transformable nucleopeptide(NLS-FF-T)self-assembled into nuclear-targeted nanoparticles with ATP binding sites encapsulated inside under aqueous conditions.By interaction with KPNA2,the NLS-FF-T transformed into a nanofibrous-based ATP trapper on the surface of tumor nuclei,which prevented the production of intracellular energy.As a result,multiple bladder tumor cell lines(T24,EJ and RT-112)revealed that the half-maximal inhibitory concentration(IC50)of NLS-FF-T was reduced by approximately 4-fold when compared to NLS-T.Following intravenous administration,NLS-FF-T was found to be dose-dependently accumulated at the tumor site of T24 xenograft mice.More significantly,this IAS system exhibited an extremely antitumor efficacy according to the deterioration of T24 tumors and simultaneously prolonged the overall survival of T24 orthotopic xenograft mice.Together,our findings clearly demonstrated the therapeutic advantages of intracellular ATP sequestration-induced mitochondriopathy-like damages,which provides a potential treatment strategy for malignancies.

关 键 词：SELF-ASSEMBLY nucleopeptide NANOMATERIAL bladder cancer mitochondriopathy 

分 类 号：R737.14[医药卫生—肿瘤] TB383.4[医药卫生—临床医学]