Ornithine dendrimers exhibit high activity as vectors for saRNA in cells and skin, highlighting their potential use in RNA vaccines.

The successful clinical translation of nonviral gene delivery systems has yet to be achieved owing to the biological and technical obstacles to preparing a safe, potent, and costeffective vector. Hyperbranched polymers, compared with other polymers, have emerged as promising candidates to address gene delivery barriers owing to their relatively simple synthesis and ease of modification, which makes them more feasible for scale-up and manufacturing. Here, we compare hyperbranched poly(amino acids) synthesised by copolymerising histidine and lysine, with hyperbranched polylysine prepared using the well-known "ultrafacile" thermal polycondensation route, to investigate the effects of histidine units on the structure and gene delivery applications of the resultant materials. The conditions of polymerisation were optimised to afford water-soluble hyperbranched polylysine-co-histidine of three different molar ratios with molecular masses varying from 13 to 30 kDa. Spectroscopic, rheological, and thermal analyses indicated that the incorporation of histidine modulated the structure of hyperbranched polylysine to produce a more dendritic polymer with less flexible branches. Experiments to probe gene delivery to A549 cells indicated that all the new hyperbranched polymers were well tolerated, but, surprisingly, the copolymers containing histidine were not more effective in transfecting a luciferase gene than were hyperbranched polylysines synthesised as established literature comparators. We attribute the variations in gene delivery efficacy to the changes induced in polymer architecture by the branching points at histidine residues, and we obtain structure-function information relating histidine content with polymer stiffness, pKa, and ability to form stable polyplexes with DNA. The results are of significance to nanomedicine design as they indicate that addition of histidine as a co-monomer in the synthetic route to hyperbranched polymers not only changes the buffering capacity of the polymer but has significant effects on the overall structure, architecture, and gene delivery efficacy.

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Novel reduction responsive oligo-β-aminoesters were successfully synthesized and condensed with siRNA through an inkjet method, thus showing promising biological response.

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