Nanozyme‐Mediated PROTACs Delivery for Targeted Protein Degradation and Ferroptosis Sensitization in Prostate Cancer

ABSTRACT Castration‐resistant prostate cancer (CRPC) remains a major clinical challenge due to its resistance to conventional androgen receptor (AR)‐targeted therapies. Proteolysis‐targeting chimeras (PROTACs) drugs, such as ARV‐771, can selectively degrade cancer‐driving proteins but face major delivery challenges that limit their efficacy and safety. Here, we report a nanoengineered PROTAC platform, ARV@MIL‐HA‐ss‐HA, that markedly improves ARV‐771 delivery, pharmacokinetics, and therapeutic efficacy. The system employs MIL‐101 nanoparticles as both a carrier and a nanozyme, modified with hyaluronic acid‐disulfide‐hyaluronic acid (HA‐ss‐HA) hydrogel to achieve CD44‐mediated tumor targeting and glutathione (GSH)‐triggered release. Leveraging the catalytic activity of MIL‐101 and the GSH‐depleting capacity of HA‐ss‐HA, ARV@MIL‐HA‐ss‐HA converts intracellular H 2 O 2 into hydroxyl radicals (·OH) and suppresses GSH levels, thereby inducing ferroptosis. Concurrently, ARV‐771‐mediated BRD4 degradation sensitizes tumor cells to ferroptosis, establishing a dual‐action 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‐PROTAC strategy as a clinically promising dual‐mechanism therapy capable of overcoming resistance in CRPC.