Shape-dependent transmembrane transport of mesenchymal stem cell membrane-coated mesoporous silica nanoparticles enhances anti-glioma therapy.

The blood-brain barrier (BBB) remains a major obstacle to effective glioma chemotherapy, and although mesenchymal stem cell (MSC) membrane (MSCM) coated nanoparticles offer a biomimetic strategy for glioma-targeted delivery, the role of particle morphology in such systems remains unclear. Herein, doxorubicin-loaded mesoporous silica nanoparticles coated with MSC membranes (MSCM@MSN@DOX) were developed with three morphologies-spherical (AR∼1), short rod-shaped (AR∼1.5), and long rod-shaped (AR∼3) to study the shape effect of MSC biomimetic drug delivery system on glioma treatment. All formulations showed successful membrane coating, retention of MSC-associated proteins, and comparable drug loading, release, and stability, enabling assessment of shape-dependent delivery behavior. Compared with AR∼1 and AR∼1.5 counterparts, AR∼3 particles exhibited enhanced motility, higher uptake by bEnd.3 and GL261 cells, improved trans-BBB transport, and deeper tumor spheroid penetration. Mechanistic studies suggested that these effects were associated with stronger nanoparticle-cell membrane interactions and morphology-dependent endocytic behavior. In an intracranial GL261 glioma model, AR∼3 particles achieved greater brain/glioma-region accumulation, more pronounced tumor growth inhibition, and extended survival, with no overt systemic toxicity under the tested regimen. These findings identify particle morphology as an important optimization parameter within the investigated MSC membrane-coated MSN system and provide a basis for shape optimization of this biomimetic nanocarrier platform for brain-targeted drug delivery.