Mortality of glioblastoma multiforme (GBM) has not improved over the last two decades despite medical breakthroughs in the treatment of other types of cancers. Nanoparticles hold tremendous promise to overcome the pharmacokinetic challenges and off-target adverse effects. However, an inhibitory effect of nanoparticles by themselves on metastasis has not been explored. In this study, we developed transferrin-conjugated porous silicon nanoparticles (Tf@pSiNP) and studied their effect on inhibiting GBM migration by means of a microfluidic-based migration chip. This platform, designed to mimic the tight extracellular migration tracts in brain parenchyma, allowed high-content time-resolved imaging of cell migration. Tf@pSiNP were colloidally stable, biocompatible, and their uptake into GBM cells was enhanced by receptor-mediated internalisation. The migration of Tf@ pSiNP-exposed cells across the confined microchannels was suppressed, but unconfined migration was unaffected. The pSiNP-induced destabilisation of focal adhesions at the leading front may partially explain the migration inhibition. More corroborating evidence suggests that pSiNP uptake reduced the plasticity of GBM cells in reducing cell volume, an effect that proved crucial in facilitating migration across the tight confined tracts. We believe that the inhibitory effect of Tf@pSiNP on cell migration, together with the drug-delivery capability of pSiNP, could potentially offer a disruptive strategy to treat GBM.Glioblastoma multiforme (GBM) is the most prevalent and biologically aggressive type of primary brain tumour in adults 1 . Standard treatment is maximal surgical resection of a tumour followed by radiotherapy and temozolomide as an adjuvant chemotherapy 2 . Despite these advanced treatments, the survival rate of GBM patients is still less than 5% over five years, with a median overall survival of merely 15-23 months 3 . The factors that contribute to the high mortality are multifactorial. First and foremost, the diffuse invasion of GBM into brain parenchyma precludes complete surgical resection which leads to high recurrence 4 . Recurring GBM are usually multi-drug resistant, rendering chemotherapy ineffective 5 . On rare occasions, the high invasion and migration potential even leads to extracranial metastases 6 .The mechanisms of GBM invasion and migration are complex and encompasses the regulation of tumour microenvironment and of the molecular arrangement within the migrating GBM cells 7 . To enable migration across the small perivascular space, GBM cells have been shown to reduce their volume by releasing cytoplasmic fluid 8 . The reduction in cell size is particularly instrumental to GBM invasion into healthy brain tissue, since www.nature.com/scientificreports www.nature.com/scientificreports/ recombinant human Fibroblast Growth Factor basic (Gibco, PHG0024), and StemPro Neural Supplement (Gibco, A10508-01). The culture media also contained GlutaMAX (Gibco, 35050-061) and penicillin/streptomycin (Gibco, 15140-122). Cells were only used betwe...