蛋白酶解靶向嵌合体(PROTAC)已成为一种有效的降解目标蛋白的策略。基于多肽的PROTAC相对于小分子基础的PROTAC具有高度特异性、低毒性和大的蛋白质相互作用表面等多个优点。但是，基于多肽的PROTAC具有一些内在的不足，如细胞穿透性差、稳定性和效力不高。在这里，我们设计了一种纳米杂交PROTAC (GNCTACs)来靶向和降解肿瘤细胞中的人表皮生长因子受体2(HER2)。利用金纳米簇(GNCs)连接HER2靶向多肽和cereblon(CRBN)靶向配体。GNCTACs可以克服基于多肽的PROTAC的固有障碍，有效将HER2靶向的多肽送入细胞质并保护其不被降解。此外，采用饥饿模仿饮食来增强细胞内摄取和蛋白酶体活性。因此，在SKBR3细胞中，超过95%的HER2被GNCTACs降解，并持续至少72小时，表现出催化反应的特点。

Proteolysis-targeting chimera (PROTAC) has emerged as a promising strategy for degrading proteins of interest. Peptide-based PROTACs offer several advantages over small-molecule-based PROTACs, such as high specificity, low toxicity, and large protein-protein interaction surfaces. However, peptide-based PROTACs have several intrinsic shortcomings that strongly limit their application including poor cell permeability and low stability and potency. Herein, we designed a nanosized hybrid PROTAC (GNCTACs) to target and degrade human epidermal growth factor receptor 2 (HER2) in tumor cells. Gold nanoclusters (GNCs) were utilized to connect HER2-targeting peptides and cereblon (CRBN)-targeting ligands. GNCTACs could overcome the intrinsic barriers of peptide-based PROTACs, efficiently delivering HER2-targeting peptides in the cytoplasm and protecting them from degradation. Furthermore, a fasting-mimicking diet was applied to enhance the cellular uptake and proteasome activity. Consequently, more than 95% of HER2 in SKBR3 cells was degraded by GNCTACs, and the degradation lasted for at least 72 h, showing a catalytic-like reaction.