An Exosome-Biomimetic Photothermal Nanocarrier for IGF2BP2 siRNA Delivery and Enhanced Ferroptosis in Head and Neck Squamous Cell Carcinoma

Head and neck squamous cell carcinoma (HNSCC) commonly develops treatment resistance, highlighting the necessity of novel therapeutic strategies. Although ferroptosis has emerged as a promising route, its regulatory determinants and effective gene delivery approaches in HNSCC remain poorly understood. In this study, we determined that the RNA-binding protein IGF2BP2 promotes ferroptosis resistance in HNSCC, at least in part by associating with increased NRF2 mRNA stability and sustaining the NRF2–SLC7A11/GPX4 antioxidant axis. Actinomycin D chase assays further support an IGF2BP2-dependent post-transcriptional regulation of NRF2 under erastin-induced ferroptotic stress. To therapeutically target this pathway, we engineered a biomimetic hybrid nanocarrier (si@PLE) by fusing M1 macrophage–derived exosomes with photothermally responsive cationic liposomes for the targeted delivery of IGF2BP2 small interfering RNA (siRNA). si@PLE exhibited favorable physicochemical properties and stability, and exosome–liposome fusion improved siRNA protection and tumor accumulation compared with that of the matched non-fused control, enabling enhanced tumor-site heating under identical irradiation conditions. In vitro and in vivo, si@PLE combined with near-infrared laser irradiation enhanced ferroptosis relative to either monotherapy, significantly suppressing tumor growth with a favorable safety profile. Collectively, these findings establish a biomimetic gene silencing–photothermal platform to sensitize HNSCC to ferroptosis by targeting the IGF2BP2–NRF2 axis.