Advancing Targeted Drug Delivery in Glioblastoma Multiforme Through Biomimetic Nanomedicine Using 3D Tumor-On-a-Chip Model.

Abstract

The prognosis of glioblastoma multiforme (GBM) remains dismal, despite standard treatment regimens. A key challenge in treating GBM is the persistence of glioma stem cells (GSCs) within the perivascular niche (PVN) - a protective tumor microenvironment (TME) that is often associated with inadequate drug penetration. Current preclinical models do not capture complexity of the human TME, particularly the vasculature and niche-specific interactions that drive GBM progression. To overcome these limitations, an innovative 3D ex-vivo tumor-on-a-chip (TOC) platform is engineered to accurately replicate the structural and functional characteristics of the PVN. Using this platform, this study demonstrates that monocyte membrane-coated nanoparticles (MoNP) effectively target the abnormal tumor microvasculature, offering a promising approach to enhance drug delivery to these hard-to-reach GSCs. The results show that the therapeutic agent verteporfin, when delivered via MoNP, significantly inhibited GSC growth and invasiveness, while the free-form drug showed minimal efficacy. Comprehensive transcriptomic profiling and cytokine analysis validated the TOC model's ability to reflect authentic GSC responses and confirmed that MoNP-mediated verteporfin delivery effectively modulates key tumor-related signaling pathways. This integrated TOC-MoNP platform represents a clinically relevant tool that bridges the gap between traditional preclinical models and human disease, providing new opportunities for developing more effective GBM therapies.