Multivalent dextran hybrids for efficient cytosolic delivery of biomolecular cargoes

The development of novel biotherapeutics based on peptides and proteins is often limited to extracellular targets, because these molecules are not able reach the cytosol. In recent years, several approaches were proposed overcome this limitation. A plethora cell-penetrating (CPPs) was developed for cytoplasmic delivery cell-impermeable cargo molecules. For many CPPs, multimerization or multicopy arrangement a scaffold resulted in improved but also higher cytotoxicity. Recently, we introduced dextran as multivalent, hydrophilic polysaccharide cell-targeting cargoes. Here, investigated covalent conjugation CPP multiple copies assessed ability molecular hybrid enter cytoplasm mammalian cells without largely compromising cell viability. As CPP, used novel, low-toxic cationic amphiphilic peptide L17E derived from M-lycotoxin. show that properties retained upon multivalent linkage dextran. Dextran-L17E efficiently mediated translocation an attached functional nucleic acid (PNA). Moreover, synthetic route established mask lysine side chains with photolabile protecting group thus opening avenues light-triggered activation cellular uptake.