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Most lysosomal storage diseases (LSDs) involve progressive central nervous system (CNS) impairment resulting from deficiency in one or more lysosomal enzymes. Treatment of neuronopathic LSDs remains a considerable challenge, as the recombinant enzymes approved to treat these conditions are ineffective in modifying CNS disease because they do not effectively cross the blood–brain barrier (BBB). To address this unmet need, we developed the Enzyme Transport Vehicle (ETV), a lysosomal enzyme fused to an engineered Fc domain that binds to the transferrin receptor and enables receptor-mediated transcytosis across the BBB. ETV fusions containing iduronate 2-sulfatase (ETV:IDS), the lysosomal enzyme whose deficiency leads to Mucopolysaccharidosis II (MPS II), were generated that have high intrinsic activity and effectively degrade accumulated substrates in IDS-deficient cells and in vivo mouse models of MPS II disease. We establish that ETV:IDS, through its interactions with TfR, significantly improves delivery of IDS to the brain without affecting the native properties of the enzyme necessary for efficient lysosomal targeting and function. This translates to robust reductions of accumulated substrates in both the brain and peripheral tissues of IDS-deficient mice and supports the potential of ETV:IDS as an intravenous monotherapy to treat peripheral and CNS manifestations of MPS II. Further, these data, together with the inherent modularity of the platform, suggest that the ETV can be harnessed more broadly to enhance brain delivery of additional lysosomal enzymes, yielding a new class of biotherapeutics for the treatment of neuronopathic LSDs.