Miktoarm Star-polypept(o)ide-Based Polyion Complex\nMicelles for the Delivery of Large Nucleic Acids

Miktoarm star polymers\nexhibit a captivating range of physicochemical\nproperties, setting them apart from their linear counterparts. This\nstudy devised a synthetic pathway to synthesize cationic miktoarm\nstars utilizing polypept(o)ides (PeptoMiktoStars), comprising 3 or\n6 polysarcosine (pSar) arms (AB<sub>3×100</sub>, AB<sub>6×50</sub>, overall 300) for shielding and a cross-linkable poly(<i>S</i>-ethylsulfonyl-l-homocysteine) (pHcy(SO<sub>2</sub>Et)<sub>20</sub>) block and a poly(l-lysine) ((pLys)<sub>20</sub>) block for nucleic acid complexation. Precise control over the DP<sub><i>n</i></sub> and narrow molecular weight distributions\n(<i>D̵</i> ≈ 1.2) were achieved for both structures.\nBoth PeptoMiktoStars efficiently complexed mRNA and pDNA into polyion\ncomplex micelles (PICMs). AB<sub>6</sub>–PICMs provided modest\n(mRNA) to high (pDNA) stability against glutathione and heparin sulfate\n(HS), while even cross-linked AB<sub>3</sub>–PICMs were susceptible\nto HS. All PICMs delivered pDNA and mRNA into D1 cells (over 80%)\nand Jurkat T cells (over 50%) in vitro. Despite payload- and cell-dependency,\nAB<sub>3</sub> showed overall higher transfection efficiency, while\nAB<sub>6</sub> demonstrated better shielding and enhanced stability.