Targeting GGT1 via RGD-modified lipid nanoparticles suppresses breast cancer lung metastasis by disrupting exosome-mediated angiogenesis

Breast cancer lung metastasis remains a major cause of mortality, largely because effective treatment options are limited. In this study, we identify gamma-glutamyltransferase 1 (GGT1) as a factor associated with breast cancer lung metastatic progression. Analyses of clinical datasets and patient specimens showed that elevated GGT1 expression was associated with lung metastasis, poorer survival, and reduced levels of the lipid peroxidation marker 4-HNE. Using MDA-MB-231 and MDA-MB-468 TNBC cell models, we found that GGT1-containing tumor-derived exosomes increased GGT1 abundance in recipient endothelial cells and promoted angiogenic phenotypes while protecting HUVECs from erastin-induced ferroptotic injury. Mechanistically, exosomal GGT1 facilitated JAK2-STAT3 association through a mechanism that was largely independent of its catalytic activity, thereby enhancing STAT3 Tyr705 phosphorylation and VEGFA transcription. In parallel, exosomal GGT1 maintained the glutathione (GSH)/GPX4 axis and reduced ferroptosis-associated stress in endothelial cells. To translate these findings therapeutically, we developed cyclic RGD peptide-functionalized lipid nanoparticles encapsulating GGT1 siRNA (RGD-LNPs-si-GGT1). LNP encapsulation prolonged systemic persistence, whereas RGD functionalization enhanced cellular uptake and tumor-associated accumulation. In both experimental and orthotopic spontaneous lung metastasis models, systemic administration of RGD-LNPs-si-GGT1 significantly reduced metastatic burden with minimal systemic toxicity. The therapeutic effect was associated with direct GGT1 silencing in tumor cells together with attenuation of GGT1-associated endothelial signaling, reduced angiogenesis, and increased ferroptosis-associated stress within the metastatic microenvironment. These findings define an exosome-mediated mechanism linking GGT1 to endothelial reprogramming and support GGT1-targeted nanodelivery as a therapeutic strategy for breast cancer lung metastasis.