Self-assembly in living cells represents one versatile strategy for drug delivery; however, it suffers from the limited precision and efficiency. Inspired by viral traits, we here report a cascade targeting-hydrolysis-transformation (THT) assembly of glycosylated
peptides in living cells holistically resembling
viral infection for efficient cargo delivery and combined
tumor therapy. We design a glycosylated
peptide via incorporating a β-
galactose-
serine residue into bola-amphiphilic sequences. Co-assembling of the glycosylated
peptide with two counterparts containing
irinotecan (IRI) or
ligand TSFAEYWNLLSP (PMI) results in formation of the glycosylated co-assemblies SgVEIP, which target
cancer cells via β-galactose-galectin-1 association and undergo
galactosidase-induced morphological transformation. While GSH-reduction causes release of IRI from the co-assemblies, the PMI moieties release p53 and facilitate cell death via binding with
protein MDM2. Cellular experiments show membrane targeting, endo-/lysosome-mediated internalization and in situ formation of nanofibers in cytoplasm by SgVEIP. This cascade THT process enables efficient delivery of IRI and PMI into
cancer cells secreting
Gal-1 and overexpressing β-
galactosidase. In vivo studies illustrate enhanced
tumor accumulation and retention of the glycosylated co-assemblies, thereby suppressing
tumor growth. Our findings demonstrate an in situ assembly strategy mimicking
viral infection, thus providing a new route for drug delivery and
cancer therapy in the future.