There is a pressing need to develop ways to deliver therapeutic macromolecules to
their intracellular targets. Certain viral and bacterial proteins are readily internalized
in functional form through lipid raft‐mediated/caveolar endocytosis, but mimicking
this process with protein cargoes at therapeutically relevant concentrations is a
great challenge. Targeting ganglioside GM1 in the caveolar pits triggers endocytosis.
A pentapeptide sequence WYKYW is presented, which specifically captures the glycan
moiety of GM1 (KD = 24 nm).
The WYKYW‐tag facilitates the GM1‐dependent endocytosis of proteins in which the cargo‐loaded
caveosomes do not fuse with lysosomes. A structurally intact immunoglobulin G complex
(580 kDa) is successfully delivered into live HeLa cells at extracellular concentrations
ranging from 20 to 160 nm, and escape of the cargo proteins to
the cytosol is observed. The short peptidic WYKYW‐tag is an advantageous endocytosis
routing sequence for lipid raft‐mediated/caveolar cell delivery of therapeutic macromolecules,
especially for cancer cells that overexpress GM1.
