南京邮电大学晁洁团队研制了用于精确肿瘤治疗的智能模块化DNA溶酶体靶向嵌合体纳米装置。相关研究成果于2024年10月21日发表在国际顶尖学术期刊《美国化学会杂志》。

溶酶体靶向嵌合体（LYTACs）已成为一种强大的方法，可以消除传统上不可治疗的细胞外肿瘤相关致病蛋白，但它们的低生物利用度和非特异性分布显著限制了它们在精确肿瘤治疗中的疗效。开发一种可以选择性靶向肿瘤组织并实现模块化设计的LYTAC系统至关重要，但具有挑战性。

该文中，研究人员开发了一种用于使用智能模块化DNA LYTAC（IMTAC）纳米器件对多致病蛋白进行肿瘤特异性降解的可编程纳米平台。研究人员使用环状DNA折纸，来整合预先设计的模块化多靶点蛋白结合位点和pH响应性蛋白降解启动子，这些启动子特异性识别肿瘤组织中的细胞表面溶酶体穿梭受体。

通过精确操纵靶向不同蛋白质的启动子和配体的化学计量和模块化，IMTAC纳米装置能够准确定位并递送到肿瘤组织中，酸性肿瘤微环境触发降解开关激活、多价结合和各种预先指定的蛋白质的有效降解。IMTAC中的组织特异性和多种配体显著提高了药物利用率，同时减少了脱靶效应。

重要的是，该系统证明了EGFR和PDL1在肿瘤组织中，用于肝细胞癌（HCC）的联合靶向和免疫治疗的协同降解能力，即使在低浓度下，也会导致明显的肿瘤坏死和体内肿瘤生长的抑制。

该研究提出了一种独特的用于构建通用、智能、模块化和简单编码的纳米平台，设计精准药物降解器和开发专有抗肿瘤药物的策略。

附：英文原文

Title: Intelligent Modular DNA Lysosome-Targeting Chimera Nanodevice for Precision Tumor Therapy

Author: Meirong Cui, Dan Zhang, Xian Zheng, Huan Zhai, Mo Xie, Qin Fan, Lianhui Wang, Chunhai Fan, Jie Chao

Issue&Volume: October 21, 2024

Abstract: Lysosome targeting chimeras (LYTACs) have emerged as a powerful modality that can eliminate traditionally undruggable extracellular tumor-related pathogenic proteins, but their low bioavailability and nonspecific distribution significantly restrict their efficacy in precision tumor therapy. Developing a LYTAC system that can selectively target tumor tissues and enable a modular design is crucial but challenging. We here report a programmable nanoplatform for tumor-specific degradation of multipathogenic proteins using an intelligent modular DNA LYTAC (IMTAC) nanodevice. We employ circular DNA origami to integrate predesigned modular multitarget protein binding sites and pH-responsive protein degradation promoters that specifically recognize cell-surface lysosome-shuttling receptors in tumor tissues. By precisely manipulating the stoichiometry and modularity of promoters and ligands targeting diverse proteins, the IMTAC nanodevice enables accurate localization and delivery into tumor tissues, where the acidic tumor microenvironment triggers degradation switch activation, multivalent binding, and efficient degradation of various prespecified proteins. The tissue-specificity and multiple ligands in IMTACs significantly improve the drug utilization rate while reducing off-target effects. Importantly, this system demonstrates the capability of collabo-rative degradation of EGFR and PDL1 in tumor tissue for combined targeting and immunity therapy of hepatocellular carcinoma (HCC), resulting in obvious tumor necrosis and inhibition of tumor growth in vivo even at low concentrations. This study presents a unique strategy for building a general, intelligent, modular, and simple encoded nanoplatform for designing precision medicine degraders and developing proprietary antitumor drugs.

DOI: 10.1021/jacs.4c10010

Source: https://pubs.acs.org/doi/abs/10.1021/jacs.4c10010