PROteolysis TArgeting Chimeras (PROTACs), a developing therapeutic tool designed to dictate target proteins for proteolysis through hijacking the ubiquitin–proteasome system, show potential for cancer therapy. However, unfavorable solubility and poor permeability of traditional PROTACs lead to low bioavailability and insufficient tumor distribution, which limit their clinical applications. Herein, we report a tridentate molecular probe (PROTAC-Cy7) by a three-in-one molecular designing strategy, which integrated a warhead that binds to MCL-1, the E3 ligase ligand pomalidomide and a heptamethine cyanine linker connecting the warhead and the ligand into the same scaffold. Then, bovine serum albumin (BSA) nanoparticles (NPs) with excellent biocompatibility, nonantigenic and biosafety were utilized to manufacture water-insoluble PROTAC-Cy7. The prepared PROTAC-Cy7@BSA NPs demonstrated tumor targeting and efficient degradation of MCL-1 through specific binding to MCL-1 receptors, which are overexpressed in multiple tumors. Moreover, PROTAC-Cy7@BSA NPs can be successfully used for near-infrared-II (NIR-II) noninvasively biomedical vascular imaging and to perform tumor resection guided by intraoperative real-time imaging. Under 808 nm laser irradiation, PROTAC-Cy7@BSA NPs exhibited synergistic Chemo-Phototherapy and showed perfect tumor suppression with 100% survival rate throughout the course of 60-day monitoring period. Our work provides a simple and feasible strategy for designing multifunctional drugs to have imaging-guided tumor-targeted multimodal therapy.

蛋白水解靶向嵌合体 (PROTAC) 是一种开发中的治疗工具，旨在通过劫持泛素-蛋白酶体系统来指示蛋白水解的靶蛋白，显示出治疗癌症的潜力。然而，传统PROTACs溶解度差、渗透性差导致生物利用度低、肿瘤分布不充分，限制了其临床应用。在此，我们通过三合一的分子设计策略报告了一种三齿分子探针（PROTAC-Cy7），它集成了一个结合 MCL-1 的弹头、E3 连接酶配体泊马度胺和一个连接弹头和配体进入同一个支架。然后，利用具有优异生物相容性、非抗原性和生物安全性的牛血清白蛋白 (BSA) 纳米颗粒 (NPs) 制造水不溶性 PROTAC-Cy7。制备的 PROTAC-Cy7@BSA NPs 通过与在多种肿瘤中过表达的 MCL-1 受体特异性结合，证明了肿瘤靶向和 MCL-1 的有效降解。此外，PROTAC-Cy7@BSA NPs 可成功用于近红外 II (NIR-II) 无创生物医学血管成像，并在术中实时成像引导下进行肿瘤切除。在 808 nm 激光照射下，PROTAC-Cy7@BSA NPs 表现出协同化学-光疗作用，并在整个 60 天的监测期内显示出完美的肿瘤抑制和 100% 的存活率。我们的工作为设计多功能药物以进行成像引导的肿瘤靶向多模式治疗提供了一种简单可行的策略。