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Glioblastoma (GBM) has limited treatment options, as the restrictive blood-brain barrier (BBB) prevents most therapeutics from accumulating at sufficient levels in the brain. Convection-enhanced delivery (CED) offers a method for administering therapeutics directly into brain tumor tissue, but free drugs can be cleared rapidly and may be toxic to off-target cells. Drug-loaded nanoparticles (NPs) are a promising platform to prolong the residence time and improve cellular targeting of therapeutics. We designed drug-conjugated NPs comprising a liposomal core modified with a layer-by-layer (LbL) polymer coating to promote tumor penetration, retention, and tumor-selective cellular association. Covalent conjugation of the potent microtubule inhibitor monomethyl auristatin-F (MMAF) to lipid headgroups resulted in striking potency against a range of patient-derived GBM cell lines compared to free MMAF and outperformed an EGFR-targeted antibody-drug conjugate of MMAF under clinical investigation. , a single CED infusion of LbL-functionalized MMAF NPs in orthotopic GBM-bearing mice displayed improved distribution and retention of both the NPs and the MMAF payload within the tumor. The LbL coating promotes selective uptake by GBM cells and prolongs drug retention, overcoming limitations of rapid clearance associated with traditional CED approaches. This treatment inhibited tumor progression and significantly extended survival compared to free MMAF, MMAF-conjugated liposomes, and an EGFR-MMAF antibody-drug conjugate. This NP platform offers a promising strategy for enhancing local GBM therapy by improving drug exposure within tumors while minimizing systemic toxicity.