Proteolysis targeting chimeras (PROTACs) have emerged as revolutionary anticancer therapeutics that degrade disease-causing proteins. However, the anticancer performance of PROTACs is often impaired by their insufficient bioavailability, unsatisfactory tumor specificity and ability to induce acquired drug resistance. Herein, we propose a polymer-conjugated PROTAC prodrug platform for the tumor-targeted delivery of the most prevalent von Hippel–Lindau (VHL)- and cereblon (CRBN)-based PROTACs, as well as for the precise codelivery of a degrader and conventional small-molecule drugs. The self-assembling PROTAC prodrug nanoparticles (NPs) can specifically target and be activated inside tumor cells to release the free PROTAC for precise protein degradation. The PROTAC prodrug NPs caused more efficient regression of MDA-MB-231 breast tumors in a mouse model by degrading bromodomain-containing protein 4 (BRD4) or cyclin-dependent kinase 9 (CDK9) with decreased systemic toxicity. In addition, we demonstrated that the PROTAC prodrug NPs can serve as a versatile platform for the codelivery of a PROTAC and chemotherapeutics for enhanced anticancer efficiency and combination benefits. This study paves the way for utilizing tumor-targeted protein degradation for precise anticancer therapy and the effective combination treatment of complex diseases.

蛋白水解靶向嵌合体 (PROTAC) 已成为降解致病蛋白质的革命性抗癌疗法。然而，PROTAC 的抗癌性能常常因其生物利用度不足、肿瘤特异性不理想以及诱导获得性耐药的能力而受到损害。在此，我们提出了一种聚合物缀合的 PROTAC 前药平台，用于肿瘤靶向递送最常见的基于 von Hippel-Lindau (VHL) 和 cereblon (CRBN) 的 PROTAC，以及降解剂和传统药物的精确共递送小分子药物。自组装的PROTAC前药纳米颗粒（NP）可以特异性地靶向肿瘤细胞并在肿瘤细胞内被激活，释放游离的PROTAC以实现精确的蛋白质降解。 PROTAC 前药 NP 通过降解含溴结构域蛋白 4 (BRD4) 或细胞周期蛋白依赖性激酶 9 (CDK9)，在小鼠模型中引起 MDA-MB-231 乳腺肿瘤更有效的消退，同时降低全身毒性。此外，我们还证明了 PROTAC 前药 NP 可以作为 PROTAC 和化疗药物共同递送的多功能平台，以提高抗癌效率和组合效益。该研究为利用肿瘤靶向蛋白降解进行精准抗癌治疗和复杂疾病的有效联合治疗铺平了道路。