De Novo Design of Hexamer‐Linker Dual‐Action Nano‐PROTAC for Tumor‐Specific Ferroptosis

Abstract Proteolysis‐Targeting Chimera (PROTAC) technology, a groundbreaking approach in drug discovery, leverages the ubiquitin‐proteasome system to degrade disease‐related proteins. Its efficacy mainly hinges on the linker design, which critically influences ternary complex (target protein‐PROTAC‐E3 ligase) stability and pharmacokinetics. However, optimizing linkers for diverse targets remains challenging due to complex structure‐activity relationships and laborious synthesis processes. Herein, we developed a self‐assembled hexamer‐linker Nano‐PROTACs, which was capable of self‐regulating spatial distances, enabling efficient degradation of proteins with different sizes. This barrel‐like hexamer‐linker has a very wide range of universality, enabling the degradation of multiple size proteins (e.g., 22, 55 and 68 kDa), with a degradation efficiency of up to 99%. More importantly, compared to a linear linker, the plasma stability of this self‐assembled hexamer‐linker increased by 48 times. Using Nano‐PROTAC with “double‐gated” system combining epidermal growth factor receptor (EGFR) targeting and ROS‐responsiveness, degradation of the challenging protein glutathione peroxidase 4 (GPX4) was achieved on mouse models, inducing tumor‐specific ferroptosis with reduced off‐target toxicity. This spatially adaptable hexamer‐linker Nano‐PROTAC system offers a universal strategy to streamline PROTAC development, highlighting its transformative potential for targeted protein degradation therapeutics.