A cRGD-engineered EV-liposome hybrid nanoplatform for targeted FAT1 mRNA delivery suppresses thyroid carcinoma metastasis by reprogramming the immunosuppressive microenvironment

Abstract This study developed a cRGD-modified mesenchymal stem cell-derived extracellular vesicle-liposome hybrid nanosystem (ELH@FAT1) for targeted delivery of FAT1 mRNA to treat thyroid carcinoma (THCA). Analysis of TCGA datasets revealed that reduced FAT1 expression is significantly associated with poor prognosis in patients with THCA. The engineered ELH@FAT1 nanosystem exhibited excellent stability and delivery efficiency, successfully restoring FAT1 expression in both THCA cells and tumor-associated macrophages (TAMs). Functional experiments revealed that ELH@FAT1 significantly suppressed C-X-C motif chemokine ligand 8 (CXCL8) secretion from M2-type TAMs, thereby disrupting the immune stemness feedback loop between TAMs and tumor stem cells (TSCs). This disruption led to diminished epithelial-mesenchymal transition (EMT), reduced cancer stemness maintenance, and inhibited metastatic capacity. Single-cell RNA sequencing (scRNA-seq) further confirmed the remodeling of the immunosuppressive tumor microenvironment (TME) and interruption of the CXCL8-mediated TAM-TSC crosstalk following ELH@FAT1 treatment. In vivo studies demonstrated that ELH@FAT1 effectively inhibited tumor growth and lung metastasis, while CXCL8 compensation or FAT1 silencing abolished these therapeutic effects. This work provides a novel nanotherapeutic strategy targeting the FAT1-CXCL8 axis to reprogram the immunosuppressive microenvironment and inhibit THCA progression.