β‐Sheet Polyelectrolyte Nanostructures: Design, Self‐Assembly, In Vitro, and In Vivo Biological Activity

Engineering macromolecular systems having protein-like intelligence is a challenging task since synthetic strategies required to impart both α-helical and β-sheet secondary structures in high molecular weight polypeptides along with polyelectrolyte characteristics in a single system. α-Helical polypetide polyelectrolytes are well-established; however, the lack of appropriate synthetic methodologies to high molecular weight β-sheet polypeptidepolyelectrolytes becomes a bottleneck in the construction of protein-mimicking synthetic nano-assemblies. Here, we report one of the first attempts to access β-sheet polypeptide core-shell polyelectrolytes based on well-defined block copolymer strategy and demonstrate their diverse action both in vitro and in vivo. Di-blockpolypeptidesare devised by constituting the first β-sheet block from ʟ-serine residue by steric-hindrance assisted ring opening polymerization (SHAROP) process and the second block from α-helical promoting ʟ-glutamate and ʟ-lysine residues. Post-polymerization deprotection has restored them into β-sheet block core-shell polyelectrolytes having anionic or cationic charges under physiological pH. These β-sheet polyelectrolytes are self-assembled into tiny 30 nm nanoparticles and behave as excellent host for loading and delivering anticancer drug doxorubicin and deep-tissue penetrable NIR biomarkers. The anionic β-sheet polyelectrolyte is non-toxic, non-hemolytic, and exhibited excellent drug delivery capabilities in the in vitro cancer cell lines and in vivo live animal (mice) model.