Degrading GPX4 via Biomimetic Nanoparticle-Mediated In Situ Synthesis of Deep-Learning-Designed Binder-Degron Chimeras for Prostate Cancer Therapy.

Glutathione peroxidase 4 (GPX4) is a central guardian against ferroptosis and a critical therapeutic target for castration-resistant prostate cancer (CRPC). However, traditional GPX4 inhibitors are often limited by irreversible covalent binding and systemic toxicity. Here, we utilized the deep learning algorithm Bindcraft to design high-affinity de novo binders targeting GPX4. To achieve GPX4 degradation, we developed a novel modality termed binder-degron chimera (bdC), which integrates a de novo-designed binder with a C-terminal combinational degron. Mechanistically, bdC recruits the CUL2-RING E3 ubiquitin ligase complex, leading to proteasome-mediated GPX4 degradation. To circumvent the delivery barriers inherent to macromolecular therapeutics, the bdC was encoded into a plasmid vector and encapsulated within a biomimetic nanocarrier featuring a PSMA-targeted and CD47-camouflaged surface (pc-CMNP). This platform enables the in situ synthesis of bdCs specifically within prostate cancer cells, driving robust GPX4 degradation and triggering potent ferroptosis. Our work establishes a versatile framework combining deep-learning generative binders, combinational degrons, and biomimetic nanotechnology to degrade intracellular targets and provides a novel therapeutic modality for CRPC.