Ferritin‐Based Nanomotors for Deep Glioblastoma Penetration and Enhanced Drug Delivery

ABSTRACT Poor penetration into tumor tissue remains a major barrier to effective nanomedicine delivery, particularly in glioblastoma multiforme (GBM). Here, nanoparticle transport was computationally studied to rationally design an ultrasmall chemotactic nanomotor that improves penetration into dense tumor tissue. The nanomotor comprises a targeting human heavy‐chain ferritin (HFn) nanocage and a catalytic cerium oxide (CeO 2 ) component. Leveraging transferrin receptor‑1 overexpression on brain microvascular endothelial cells and GBM cells, HFn enables transport across an in vitro blood–brain barrier (BBB) model and accumulation in GBM spheroids. The CeO 2 domain catalyzes hydrogen peroxide decomposition in the tumor‑mimicking microenvironment, generating oxygen and imparting directional propulsion along H 2 O 2 gradients. In chemotaxis assays, the nanomotors actively migrated toward localized H 2 O 2 sources and GBM cells embedded in Matrigel. In large U87 spheroids (>400 µm), HFn@CeO 2 nanomotors penetrated deeply and distributed throughout the spheroid core, whereas non‑propelled HFn nanocarriers remained confined mainly to the periphery. Doxorubicin‑loaded nanomotors (HFn@CeO 2– DOX) achieved substantially enhanced intratumoral DOX distribution and reduced IC 50 (0.33 µM) compared with HFn–DOX (1.13 µM) and free DOX (1.75 µM) in GBM spheroids. These results provide a promising basis for future in vivo evaluation in brain tumor therapy.