Here, we used single-domain antibodies (sdAbs, VHHs) capable of transmigrating the BBB by RMT (referred to as ‘BBB Trojans’) [9–11], to functionalize CNS delivery of iduronate-2-sulfatase (IDS), an enzyme deficient in patients with mucopolysaccharidosis type II (MPS II; Hunter syndrome). Here, IDS is linked to mucopolysaccharidosis type 2.