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Proteolysis\u2010targeting chimeras (PROTACs) drugs, such as ARV\u2010771, can selectively degrade cancer\u2010driving proteins but face major delivery challenges that limit their efficacy and safety. Here, we report a nanoengineered PROTAC platform, ARV@MIL\u2010HA\u2010ss\u2010HA, that markedly improves ARV\u2010771 delivery, pharmacokinetics, and therapeutic efficacy. The system employs MIL\u2010101 nanoparticles as both a carrier and a nanozyme, modified with hyaluronic acid\u2010disulfide\u2010hyaluronic acid (HA\u2010ss\u2010HA) hydrogel to achieve CD44\u2010mediated tumor targeting and glutathione (GSH)\u2010triggered release. Leveraging the catalytic activity of MIL\u2010101 and the GSH\u2010depleting capacity of HA\u2010ss\u2010HA, ARV@MIL\u2010HA\u2010ss\u2010HA converts intracellular H\n                    <jats:sub>2<\/jats:sub>\n                    O\n                    <jats:sub>2<\/jats:sub>\n                    into hydroxyl radicals (\u00b7OH) and suppresses GSH levels, thereby inducing ferroptosis. Concurrently, ARV\u2010771\u2010mediated BRD4 degradation sensitizes tumor cells to ferroptosis, establishing a dual\u2010action synergistic mechanism. In vitro and in vivo studies in CRPC models confirmed efficient BRD4 degradation, enhanced ferroptotic cell death, and superior antitumor efficacy with minimal systemic toxicity. Our findings position this nano\u2010PROTAC strategy as a clinically promising dual\u2010mechanism therapy capable of overcoming resistance in CRPC.\n                  <\/jats:p>","DOI":"10.1002\/anie.6657773","type":"journal-article","created":{"date-parts":[[2026,3,23]],"date-time":"2026-03-23T16:36:11Z","timestamp":1774283771000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Nanozyme\u2010Mediated PROTACs Delivery for Targeted Protein Degradation and Ferroptosis Sensitization in Prostate Cancer"],"prefix":"10.1002","volume":"65","author":[{"given":"Chenyuan","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Urology Renmin Hospital of Wuhan University School of Pharmaceutical Sciences Wuhan University  Wuhan China"},{"name":"Department of Nuclear Medicine Zigong First People's Hospital Zigong Academy of Medical Sciences  Zigong 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