Proteolysis targeting chimeras (PROTACs) have recently emerged as promising therapeutic agents for cancer therapy. However, their clinical application is considerably hindered by the poor membrane permeability and insufficient tumor distribution of PROTACs. Here we proposed a nanoengineered targeting strategy to construct a self-assembled affibody-PROTAC conjugate nanomedicine (APCN) for tumor-specific delivery of PROTACs. As proof of concept, a hydrophobic PROTAC MZ1 (a bromodomain-containing protein 4 degrader) was selected to couple with a hydrophilic affibody Z_HER2:342 (an affinity protein of human epidermal growth factor receptor 2, HER2) via a smart linker containing disulfide bond to form an amphiphilic Z_HER2:342-MZ1 conjugate. It spontaneously self-assembled into nanoparticles (Z_HER2:342-MZ1 APCN) in water. Upon the excellent targeting property of Z_HER2:342 and HER2 receptor-mediated endocytosis, Z_HER2:342-MZ1 APCN was accumulated in tumor sites and internalized by cancer cells effectively in vitro. Under the intracellular high level of glutathione (GSH), Z_HER2:342-MZ1 APCN released MZ1 to specifically degrade bromodomain-containing protein 4 (BRD4) and subsequently induced BRD4 deficiency-mediated apoptosis of cancer cells. By the tail-vein injection, Z_HER2:342-MZ1 APCN showed the outstanding tumor-specific targeting ability, drug accumulation capacity, enhanced BRD4 degradation and antitumor efficacy in vivo for an HER2-positive SKOV-3 tumor model. Such an affibody mediated nanoengineered strategy would facilitate the application of PROTACs for targeted cancer therapy.