In summary, HPAE-EB has ideal biophysical properties to navigate the hurdles for efficient and cytocompatible gene delivery, in this case by targeting the therapeutically relevant exon 80 of the COL7A1 gene, showing its potential for excision of mutation sites as a therapeutic strategy in RDEB using CRISPR–Cas9. Here, COL7A1 is linked to recessive dystrophic epidermolysis bullosa.