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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 3Dex‐vivotumor‐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. 

Abstract The perivascular niche (PVN) is a glioblastoma tumor microenvironment (TME) that serves as a safe haven for glioma stem cells (GSCs), and acts as a reservoir that inevitably leads to tumor recurrence. Understanding cellular interactions in the PVN that drive GSC treatment resistance and stemness is crucial to develop lasting therapies for glioblastoma. The limitations of in vivo models and in vitro assays have led to critical knowledge gaps regarding the influence of various cell types in the PVN on GSCs behavior. This study developed an organotypic triculture microfluidic model as a means to recapitulate the PVN and study its impact on GSCs. This triculture platform, comprised of endothelial cells (ECs), astrocytes, and GSCs, is used to investigate GSC invasion, proliferation and stemness. Both ECs and astrocytes significantly increased invasiveness of GSCs. This study futher identified 15 ligand‐receptor pairs using single‐cell RNAseq with putative chemotactic mechanisms of GSCs, where the receptor is up‐regulated in GSCs and the diffusible ligand is expressed in either astrocytes or ECs. Notably, the ligand–receptor pair SAA1‐FPR1 is demonstrated to be involved in chemotactic invasion of GSCs toward PVN. The novel triculture platform presented herein can be used for therapeutic development and discovery of molecular mechanisms driving GSC biology.