靶向蛋白水解嵌合体(PROTAC)是新兴的蛋白质降解策略，在疾病相关的不可成药蛋白的降解中展现了突出优势，成为最具潜力的疾病治疗方式之一。然而PROTAC分子在降解疾病细胞中表达异常的蛋白的同时也降解了正常细胞中的靶蛋白，扰乱了正常细胞的代谢，增加了生理毒性，其不可控性限制了其在疾病治疗中的应用。为实现肿瘤细胞选择性的蛋白降解，基于肿瘤细胞中存在过表达的组织蛋白酶B(CTSB)，本文制备CTSB激活的原位自组装多肽分子，并在该分子上修饰溴结构域蛋白4(BRD4)的配体或von Hippel-Lindau (VHL) E3泛素连接酶配体，得到SA-BRD4和SA-VHL。SA-BRD4和SA-VHL在进入肿瘤细胞后，在CTSB激活后可发生生物正交的缩合反应形成环状二聚体，该二聚体通过π-π堆积作用，原位自组装形成具有蛋白降解活性的纳米结构PROTACs并高效降解BRD4蛋白，而在正常细胞中不发挥作用，实现细胞选择性的BRD4降解。

PROTAC is a newly-developing protein degradation strategy showing prominent advantage in degradation of undruggable protein, which becomes one of potential disease therapies. However, PROTAC not only degrades the abnormally expressing targeted protein in disease cells but also degrades the targeted protein in normal cells. This phenomenon disturbs the metabolism and increases the cytotoxicity, and its uncontrollablity limits the application of PROTACs in disease therapy. To realize the cell-selective protein degradation, considering the over-expressing of CTSB in cancer cells, we synthesis CTSB-activated in situ self-assembling peptide. We modify the self-assembling peptide with the ligand of BRD4 or the ligand of VHL E3 ubiquitin ligase, yielding SA-BRD4 and SA-VHL. As SA-BRD4 and SA-VHL permeate into the cancer cells, they are activated by CTSB and are able to condensate into dimers that can later self-assemble into nano-PROTACs by π-π stacking and efficiently degrade BRD4. While they can’t degrade BRD4 in normal cells, showing the cell-selective BRD4 degradation.