Biomaterial-Enabled Delivery Strategies to Overcome Treatment Resistance in Medulloblastoma.
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Multimodal therapy has improved survival in medulloblastoma (MB), yet recurrence, neuraxis dissemination, and treatment-related late effects remain major challenges. Treatment resistance reflects clonal evolution, drug efflux, altered DNA-damage and apoptotic responses, treatment-persistent cells, the tumor microenvironment, and inadequate active-drug exposure across the blood-brain barrier (BBB), postoperative residual compartments, and cerebrospinal fluid (CSF) spaces. Biomaterials can modify intracranial distribution, local retention, combination exposure, and intracellular cargo release. This review evaluates direct MB evidence for polymeric and lipid nanomedicines, biomimetic and virus-derived platforms, magnetic materials, extracellular vesicles, and hydrogels across intracranial solid lesions, postoperative residual disease, and neuraxis dissemination, while defining the limits of extrapolation from related tumors. Systemic nanomedicines currently provide the broadest evidence chain from formulation optimization to brain or tumor exposure, target modulation, and antitumor activity. Disease-matched studies also support active transendothelial transport and intrathecal nanoparticle therapy for metastatic MB. Most evidence remains preclinical; direct evidence of reversal of established treatment resistance is limited, and human studies largely assess route feasibility and safety. Progress will require quantitative active-cargo pharmacokinetics and pharmacodynamics, disease- and route-matched models, juvenile neurodevelopmental safety testing, and defined product quality attributes to determine whether these platforms can widen the therapeutic window or restore treatment sensitivity.