Fig. 1

Concept of the reversible glycosidic switch. a A water/lipid soluble switch is conjugated to a hydrophobic cargo via a cue-responsive linker able to release the cargo at a specific site. b We employed a glycosidic switch that can be esterified in acidic methanol to a lipid-soluble form (shown in orange) to facilitate active loading across the liposome membrane. At a high internal pH in the aqueous lumen of the liposomes, the glycosidic switch is spontaneously saponified to the water-soluble form (shown in blue), resulting in strong retention of the molecular cargo. The cargo loaded in the liposomes is stable in the circulation and can be delivered to target cells for cellular uptake and lysosomal degradation. The cue-responsive trigger (shown in grey) responds to beta-glucuronidase (shown in pink) in lysosomes to release the parental cargo within the cells