pH-Activatable engineered nanoparticle-based selective hexokinase 2 degrader provokes GSDME-dependent pyroptosis for cancer therapy

Proteolysis targeting chimeras (PROTACs) technology has been developed as an exquisite promising approach for targeted protein degradation by hijacking the cellular ubiquitin-proteasome system (UPS). However, traditional PROTACs often suffer from insufficient tumor accumulation, unfavorable membrane penetration, and always-on biological activity, limiting their antitumor performance. Herein, we report a novel pH-activatable engineered nanoparticle-based selective hexokinase 2 degrader (Nano-PROTACs) for cancer therapy. Nano-PROTACs were constructed by conjugating PEI-based PROTACs to amphiphilic nanoparticles <i>via</i> acid-detachable <i>cis</i>-aconitic anhydride (CAA) bonds. Then, Nano-PROTACs allowed PEI-based PROTACs release within the tumor acidic microenvironment, which bounded to HK-2 and recruited cereblon (CRBN) to provoke HK-2 ubiquitination for achieving HK-2 degradation <i>via</i> UPS. Interestingly, Nano-PROTACs specifically evoked GSDME-mediated pyroptosis to enhance cancer therapy. Thus, Nano-PROTACs effectively inhibited the growth of CT26 tumors and prevented tumor growth and lung metastasis in the orthotopic 4T1-luciferase tumor-bearing mouse model. Taken together, this study might offer a nanoparticle-based PROTACs platform for advancing selective protein of interest (POI) degradation in cancer therapy.