cRGD-modified liposomes with enhanced blood-tumor barrier penetration enabling NO-mediated modulation of chemoresistance in orthotopic glioblastoma

cRGD-modified ITC NPs target αvβ3 integrin for BBB/BTB traversal in GBM. • NIR-triggered ITC NPs combine TMZ chemotherapy and phototherapy. • ITC NPs generate NO in situ to improve perfusion and modulate resistance. • NIR-II fluorescence imaging and LSCI enable GBM diagnosis and perfusion monitoring. Glioblastoma (GBM) remains one of the most lethal brain malignancies, largely due to the blood-brain barrier (BBB) and the pathologically heterogeneous blood-tumor barrier (BTB), which severely restrict drug delivery. To achieve targeted BBB/BTB traversal, we developed cRGD-modified ICG/TMZ@Lips nanoparticles (ITC NPs). The nanoplatform actively targets αvβ3 integrin overexpressed on tumor endothelial cells and GBM cells, thereby promoting receptor-mediated transport and tumor penetration. Under near-infrared (NIR) irradiation, ITC NPs trigger temozolomide (TMZ) release and photo-responsive NO-associated effects. These effects are accompanied by heat shock protein 70 (HSP70) downregulation and modulation of resistance-related pathways, which may contribute to enhanced chemosensitivity. Furthermore, we integrated near-infrared II (NIR-II) fluorescence imaging with laser speckle contrast imaging (LSCI) for real-time GBM diagnosis and perfusion monitoring. To the best of our knowledge, among existing BBB/BTB traversal strategies, this is the first study to apply cRGD peptide for specific and efficient BBB/BTB penetration in GBM therapy. This strategy directly addresses the fundamental limitations imposed by the heterogeneous and efflux-active BTB, offering a precise nanomedicine approach for improved therapeutic outcomes. Download: Download high-res image (353KB) Download: Download full-size image