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.