近日，中国科学院杭州医学研究所张鹏晖及其研究小组研究出可编程的圆形多价纳米靶向嵌合体（mNbTACs），用于多受体介导的蛋白质降解和靶向药物递送。2024年10月15日出版的《德国应用化学》发表了这项成果。

研究人员表示，多特异性治疗在药物递送、蛋白质降解和细胞募集方面具有重要的前景，可以解决肿瘤异质性、耐药性和免疫逃避的临床问题。然而，其模块化工程仍然具有挑战性。

该课题组开发了一个靶向降解平台，称为多价纳米体靶向嵌合体（mNbTACs），通过用DNA打印技术在圆形模板上编码不同的纳米体密码子。同种或异种mNbTACs以多价方式特异性识别膜靶标，同时招募清除率受体，以高效率和选择性地促进网格蛋白/小泡依赖的内吞和溶酶体降解多种蛋白质。

课题组证明了一种名为Doxo-mvNbsPPH的双特异性负载多柔比星的mNbTAC在肿瘤部位被动积累，特异性地与PD-L1和HER2靶点相互作用，并迅速转运到溶酶体中，诱导有效的免疫原性细胞死亡，减轻免疫检查点逃避。先天免疫和适应性免疫协同增强，促进CD8+ T细胞在肿瘤微环境中的浸润和增殖（增加11倍），具有高毒性和低衰竭，最终增强抗肿瘤疗效。

他们的mNbTAC平台提供了具有可变价和程序化种类的多特异性治疗方法，而它通过多受体介导的内吞作用和溶酶体降解诱导靶向蛋白质降解，而不需要溶酶体靶向受体，代表了利用细胞外蛋白质组进行疾病治疗的通用和模块化工具。

附：英文原文

Title: Programmable Circular Multivalent Nanobody-Targeting Chimeras (mNbTACs) for Multireceptor-Mediated Protein Degradation and Targeted Drug Delivery

Author: Shiqi Jiang, Xinru Lv, Zhenlin Ouyang, Hongli Chi, Yuchen Zeng, Yani Wang, Jiaxuan He, Jinling Chen, Jingyi Chen, Keli An, Ming Cheng, Yurong Wen, Juan Li, Penghui Zhang

Issue&Volume: 2024-10-15

Abstract: Multispecific therapeutics hold significant promise in drug delivery, protein degradation, and cell recruitment to address clinical issues of tumor heterogeneity, resistance, and immune evasion. However, their modular engineering remains challenging. We developed a targeted degradation platform, termed multivalent nanobody-targeting chimeras (mNbTACs), by encoding diverse nanobody codons on a circular template using DNA printing technology. The homo- or hetero- mNbTACs specifically recognized membrane targets in a multivalent manner and simultaneously recruited scavenger receptors to favor clathrin-/caveolae-dependent endocytosis and lysosomal degradation of multiple proteins with high efficiency and selectivity. We demonstrated that a bispecific doxorubicin-loaded mNbTAC, named Doxo-mvNbsPPH, passively accumulated at tumor sites, specifically interacted with PD-L1 and HER2 targets, and was rapidly transported into lysosome, inducing potent immunogenic cell death and alleviating immune checkpoint evasion. The synergistic boosting of innate and adaptive immunity promoted the infiltration and proliferation of CD8+ T cells in tumor microenvironment (an 11-fold increase) with high toxicity and low exhaustion, eventually enhancing antitumor efficacy. Our mNbTAC platform provides multispecific therapeutics with variable valences and programmed species, whereas it induces targeted protein degradation through multireceptor-mediated endocytosis and lysosomal degradation without the need for lysosome-targeting receptors, representing a general and modular tool to harness extracellular proteome for disease treatment.

DOI: 10.1002/anie.202407986

Source: https://onlinelibrary.wiley.com/doi/10.1002/anie.202407986