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

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.