Glyco Ionic Liquids as Novel Nanoparticle Coatings to Enhance Triple-Negative Breast Cancer Drug Delivery.

Targeted drug delivery seeks to revolutionize disease treatment by enhancing therapeutic efficacy and specificity. However, developing and achieving precisely targeted delivery remains a significant challenge, particularly in cancers such as triple-negative breast cancer (TNBC), which lack traditional markers for targeted delivery. TNBC cells overexpress glucose transport proteins (GLUTs) on their surfaces, providing an opportunity for targeting. Herein, sugar-based ionic liquids (Glyco-ILs or GILs) are developed and used to modify poly (lactic-co-glycolic acid) (PLGA) nanocarriers (NPs), show enhanced affinity and selectivity towards TNBC cells and human and mouse erythrocytes. Inhibition assays, molecular docking simulations, and liquid chromatography-mass spectrometry (LCMS) analysis data show that the enhanced nanoparticle affinity for TNBC cells is likely due to a combination of specific binding interactions with GLUT transporters and endocytosis. The observed RBC affinity is evidenced to be driven by interactions with RBC membrane GLUTs along with their unique serum protein corona on the nanoparticle surface. In vivo, experiments in a healthy BALB/c mouse model show that Glyco-IL-NPs demonstrate longer retention time in the bloodstream and a significant reduction in liver accumulation relative to the control. These findings suggest that Glyco-IL-modified PLGA nanoparticles (GIL-NPs) hold a promising approach for selective drug delivery, particularly in cells that overexpress GLUTs.