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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\u2010affinity de novo binders targeting GPX4. To achieve GPX4 degradation, we developed a novel modality termed binder\u2010degron chimera (bdC), which integrates a de novo\u2010designed binder with a C\u2010terminal combinational degron. Mechanistically, bdC recruits the CUL2\u2010RING E3 ubiquitin ligase complex, leading to proteasome\u2010mediated 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\u2010targeted and CD47\u2010camouflaged surface (pc\u2010CMNP). 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\u2010learning generative binders, combinational degrons, and biomimetic nanotechnology to degrade intracellular targets and provides a novel therapeutic modality for CRPC.<\/jats:p>","DOI":"10.1002\/advs.77932","type":"journal-article","created":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T18:00:31Z","timestamp":1790532031000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Degrading GPX4 via Biomimetic Nanoparticle\u2010Mediated In Situ Synthesis of Deep\u2010Learning\u2010Designed Binder\u2010Degron Chimeras for Prostate Cancer Therapy"],"prefix":"10.1002","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0647-690X","authenticated-orcid":false,"given":"Si\u2010Han","family":"Zhang","sequence":"first","affiliation":[{"name":"Department and Institute of Urology, Tongji Hospital, Tongji Medical College Huazhong University of Science and Technology  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