Ferritin-Conjugated PROTAC Strategy for ERCC1/XPF Degradation and Platinum Sensitization in Resistant Tumors.

Cisplatin resistance remains a major clinical challenge in cancer therapy, often driven by the upregulation of DNA repair pathways. Here, we present a dual-functional nanotherapeutic system (HFn-NERiP-Pt(IV)) combining a glutathione-responsive PROTAC (NERiP) with a ferritin nanocarrier for targeted ERCC1/XPF degradation and enhanced platinum delivery. NERiP selectively degrades ERCC1/XPF upon release in reductive tumor environments, suppressing nucleotide excision repair and enhancing platinum cytotoxicity. The ferritin nanocage enables tumor-selective codelivery of NERiP and a Pt(IV) prodrug through thiol-maleimide conjugation and pH-triggered release. In vitro and in vivo studies demonstrate effective ERCC1/XPF degradation, increased DNA damage, and significant tumor regression in cisplatin-resistant esophageal squamous cell carcinoma. This rationally designed nanoconjugate integrates targeted protein degradation and chemopotentiation with improved pharmacokinetics, offering a promising strategy to overcome chemoresistance.