Multifunctional Engineered Metal-Organic Frameworks as Targeted Protein Degraders for Augmenting Cancer Therapy via Hexokinase 2 Degradation and Provoking Cuproptosis.

Cuproptosis, a newly identified form of copper-dependent programmed cell death, has emerged as a potential therapeutic strategy for cancer treatment. However, its antitumor efficacy was strictly limited by dysregulated glycolytic metabolism of tumor cells. Herein, we proposed multifunctional copper-based nano-PROTACs (CHNDs) to degrade hexokinase 2 (HK-2) and amplify cuproptosis for cancer therapy via dual mitochondrial energy depletion. Our initial evaluation indicated that polyethyleneimine (PEI)-based nano-PROTACs (PHDs) triggered HK-2 degradation via the ubiquitin-proteasome system (UPS). PHDs reduced HK-2 expression to 43.7% in 4T1 cells and 42.1% in CT26 cells, which consequently impaired glycolysis in tumor cells. Furthermore, copper ion release from CHNDs in a controlled manner and the glucose metabolism homeostasis interference by PHDs orchestrally induced effective cuproptosis and glycolysis inhibition for suppressing development and metastasis of tumor cells. Notably, CHNDs markedly inhibited the growth of murine colon and breast tumors by simultaneously disrupting mitochondrial respiration and glycolysis, resulting in tumor inhibition rates of 76.6% and 55.3%, respectively, and extending the median survival of CT26 tumor-bearing mice from 21 to 29 d. Our designed multifunctional engineered nanoparticle-based targeted protein degraders facilitated a new paradigm for precise oncology and proteolysis-targeting chimera (PROTAC) development.