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However, they often encounter limitations in in vivo applications due to poor solubility, low cellular permeability, unfavorable pharmacokinetics, and more. To address these challenges, we developed a multifunctional \u201conion-like\u201d nanoplatform, PB@SiO2@MnO2@dGPX4\/PVP (PMDP), which delivers a glutathione peroxidase 4 (GPX4) PROTAC degrader, dGPX4, to induce ferroptosis in triple-negative breast cancer cells. PMDP consists of Prussian blue (PB) nanoparticles that are coated with a protective SiO2 layer and an MnO2 shell. The nanoparticles are encapsulated with polyvinylpyrrolidone after dGPX4 adsorbs onto the surface. The resulting PMDP enhances tumor enrichment and cellular uptake of dGPX4. It also depletes glutathione and catalyzes Fenton-like reactions in cancer cells, generating reactive oxygen species (ROS). PB\u2019s near-infrared (NIR) photothermal capability simultaneously facilitates this reaction and enables mild photothermal therapy. Concurrently, dGPX4 effectively degrades the key anti-ferroptosis protein GPX4, thereby disrupting the cellular antioxidant defense system. Studies demonstrate that PMDP induces a \u201cROS storm\u201d, lipid peroxidation, and mitochondrial damage, triggering efficient ferroptosis and significantly inhibiting tumor growth in TNBC models. This research shows the potential to integrate targeted protein degradation with multiple nanomedicine technologies, offering a promising combination strategy for cancer therapy.<\/jats:p>","DOI":"10.1021\/acsami.6c15772","type":"journal-article","created":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T19:02:49Z","timestamp":1792004569000},"page":"57204-57221","source":"Crossref","is-referenced-by-count":0,"title":["PROTAC-Loaded Nanoparticles Induce a \u201cROS Storm\u201d through Targeted Degradation of GPX4 in Combination with a Mild Photothermal\/Fenton-like Reaction for the Treatment of Triple-Negative Breast Cancer"],"prefix":"10.1021","volume":"18","author":[{"given":"Zekun","family":"Xu","sequence":"first","affiliation":[{"name":"Hubei University , , ,","place":["Wuhan, P. R. China, 430062"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinyu","family":"Wang","sequence":"additional","affiliation":[{"name":"Hubei University of Technology , , ,","place":["Wuhan, P. R. China, 430068"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuhong","family":"Li","sequence":"additional","affiliation":[{"name":"Hubei University of Technology , , ,","place":["Wuhan, P. R. China, 430068"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tao","family":"Liao","sequence":"additional","affiliation":[{"name":"Hubei University of Technology , , ,","place":["Wuhan, P. R. China, 430068"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying","family":"Kuang","sequence":"additional","affiliation":[{"name":"Hubei University of Technology , , ,","place":["Wuhan, P. R. China, 430068"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kai","family":"Wang","sequence":"additional","affiliation":[{"name":"Hubei University , , ,","place":["Wuhan, P. R. China, 430062"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3500-340X","authenticated-orcid":true,"given":"Cao","family":"Li","sequence":"additional","affiliation":[{"name":"Hubei University , , ,","place":["Wuhan, P. R. China, 430062"]},{"name":"Hubei University of Technology , , ,","place":["Wuhan, P. R. 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