This report highlights the importance of hydrophobic groups mimicking the side chains of aromatic amino acids, which are tryptophan, phenylalanine, and tyrosine, in guanidinium bearing poly(methacrylamide)s for the design of non‐viral gene delivery agents. Guanidinium containing methacrylamide terpolymers are prepared by aqueous reversible addition–fragmentation chain transfer (aRAFT) polymerization with different hydrophobic monomers, N‐(2‐indolethyl)methacrylamide (IEMA), N‐phenethylmethacrylamide (PhEMA), or N‐(4‐hydroxyphenethyl)methacrylamide (PhOHEMA) by aiming similar contents. The well‐defined polymers are obtained with a molar mass of ≈15 000 g mol−1 and ≈1.1 dispersity. All terpolymers demonstrate almost comparable in vitro cell viability and hemocompatibility profiles independent of the type of side chain. Although they all form positively charged, enzymatically stable polyplexes with plasmid DNA smaller than 200 nm, the incorporation of the IEMA monomer improve these parameters by demonstrating a higher DNA binding affinity and forming nanoassemblies of about 100 nm. These physicochemical characteristics are correlated with increased transfection rates in CHO‐K1 cells dependent on the type of the monomer and the nitrogen to phosphate (N/P) ratio of the polyplexes, as determined by luciferase reporter gene assays.

Inside Cover: In article number 2000580 by Dagmar Fischer, Kalina Peneva, and co‐workers, guanidinium, containing methacrylamide terpolymers with three different side chains mimicking hydrophobic amino acid residues, are designed to evaluate to what extent does the identity of these hydrophobic groups influence the binding, protection, and transfection of DNA.

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