Non-covalent delivery of native proteins and peptides by phenylboronic cell-penetrating poly(disulfide)s

Poly(disulfide)s have been proposed as delivery carriers, yet their design for native protein delivery without covalent conjugation remain elusive and challenging. Here, we present a type of poly(disulfide)s randomly copolymerized from cell-penetrating cyclic five-membered disulfide (CFMD) monomer (M1) and phenylboronic CFMD monomer (M2) by ring-opening polymerization. The resulted poly(disulfide)s can directly complex a broad range of native, unmodified proteins and peptides via multiple non-covalent forces, regardless of their chemical structure, molecular weight and isoelectric point. The complexation between poly(disulfide)s and proteins can be predominantly internalized by cells via strain-promoted, thiol-mediated translocation, bypassing the classical endocytic pathway. The degradation of the poly(disulfide) is induced by rich intracellular glutathione, thereby timely releasing protein or peptide cargoes in their active form and minimize the cytotoxicity of the carrier. Of note, the surface coating of poly(disulfide) complexes by hyaluronic acid enables the systemic delivery of functional proteins, demonstrating their therapeutic potentials in vivo.