RGD-Lipo@GOx: A nanotherapeutic strategy for targeting glycolysis and immune evasion in triple-negative breast cancer.

Triple-negative breast cancer (TNBC) is a highly aggressive malignancy driven by glycolysis and immune evasion, with limited therapeutic options. This study develops RGD-modified glucose oxidase-loaded liposomes (RGD-Lipo@GOx) to target TNBC by modulating the MIF/NR3C2 axis, aiming to inhibit glycolysis and remodel the immune microenvironment. RGD-Lipo@GOx exhibited high encapsulation efficiency and tumor specificity. Bioinformatics analyses confirmed upregulated MIF and downregulated NR3C2 in TNBC. In vitro, RGD-Lipo@GOx suppressed glycolysis, migration, and invasion in MDA-MB-231 and BT-549 cells, upregulating NR3C2 and inhibiting MIF and PI3K/AKT signaling. In vivo, a TNBC xenograft model demonstrated enhanced tumor targeting, significant growth inhibition, and reduced glycolysis without systemic toxicity. These results highlight RGD-Lipo@GOx's potential as a nanotherapeutic platform that disrupts TNBC's metabolic and immune evasion mechanisms. Its high efficacy and safety suggest potential for clinical translation, particularly in combination with immunotherapies, and applicability to other glycolysis-driven cancers, advancing nanomedicine for precision oncology.