哈尔滨医科大学Wanhai Xu等研究人员合作发现，可转化核肽纳米颗粒诱导的线粒体病变样损伤可实现膀胱癌的靶向治疗。2024年1月22日，国际知名学术期刊《国家科学评论》在线发表了这一成果。

利用体内自组装纳米材料的优势，研究人员设计了一种细胞内三磷酸腺苷（ATP）螯合（IAS）系统，在暴露有ATP结合位点的肿瘤核表面特异性地构建纳米纤维状纳米结构，通过诱导线粒体病变样损伤高效抑制膀胱癌。简而言之，所报道的可转化核肽（NLS-FF-T）在水溶液条件下自组装成核靶向纳米颗粒，其内部包裹着ATP结合位点。通过与KPNA2相互作用，NLS-FF-T在肿瘤细胞核表面转化为基于纳米纤维的ATP捕获器，阻止了细胞内能量的产生。因此，多个膀胱肿瘤细胞系（T24、EJ和RT-112）显示，NLS-FF-T的半抑制浓度（IC50）比NLS-T降低了约4倍。

静脉给药后，NLS-FF-T在T24异种移植小鼠肿瘤部位的蓄积呈剂量依赖性。更重要的是，根据T24肿瘤的恶化情况，这种IAS系统表现出极强的抗肿瘤功效，同时延长了T24异位移植小鼠的总体存活时间。总之，这些研究结果清楚地表明了细胞内ATP螯合诱导线粒体病变样损伤的治疗优势，这为恶性肿瘤提供了一种潜在的治疗策略。

据悉，线粒体病变引起的ATP耗竭已被认为是控制肿瘤生长的一种有效方法。然而，在复杂的生物环境中选择性地封存或耗尽ATP仍是一个巨大的挑战。

附：英文原文

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

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

Issue&Volume: 2024-01-22

Abstract: Mitochondriopathy inspired adenosine triphosphate (ATP) depletions has been recognized as a powerful way for controlling tumor growth. Nevertheless, selective sequestration or exhaustion of ATP under complex biological environment 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 nuclear with exposed ATP binding site, 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 site encapsuled inside under aqueous conditions. By interaction with KPNA2, the NLS-FF-T transformed into nanofibrous-based ATP trapper on the surface of tumor nuclear, which prevented the intracellular energy production. 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 intravenously administration, NLS-FF-T was found to be dose-dependently accumulated at 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.

DOI: 10.1093/nsr/nwae028

Source: https://dx.doi.org/10.1093/nsr/nwae028