Acid-activated Fe-doped layered double hydroxides coupling FAK blockade and chemodynamic therapy for triple-negative...

Triple-negative breast cancer (TNBC) remains a highly aggressive malignancy with limited therapeutic targets and frequent treatment resistance. Focal adhesion kinase (FAK), encoded by PTK2, regulates tumor-cell survival and motility, but the efficacy of small-molecule FAK inhibitors is limited by insufficient tumor accumulation. Here, we developed an acid-responsive Fe-doped LDH nanoplatform incorporating the FAK inhibitor Y15, termed Y15@LDH, for synergistic TNBC therapy. Y15 was introduced during LDH formation, enabling its integration into the Fe-doped LDH framework. Under acidic tumor-associated conditions, Y15@LDH underwent accelerated disassembly and synchronously released Y15 and iron ions. Released Y15 inhibited FAK Tyr397 phosphorylation and downstream AKT signaling, whereas iron ions catalyzed endogenous H₂O₂ to generate hydroxyl radicals (·OH) through Fenton-like reactions, inducing ROS accumulation, mitochondrial dysfunction and DNA damage. This dual mechanism further promoted immunogenic damage-associated signals, including calreticulin exposure, ATP secretion and HMGB1 release. In vitro and in vivo studies demonstrated that Y15@LDH effectively suppressed 4 T1 tumor progression, prolonged survival and showed favorable biosafety. This study provides a PTK2/FAK-guided nanotherapeutic strategy integrating FAK blockade and Fe-mediated chemodynamic therapy for TNBC treatment.