Off-to-On Switching of Transcription Activity in Condensed pDNA within Polyplex Micelles Triggered by Lysine Chemical Acetylation

Off-to-on switching of transcriptional activity was achieved in a polyplex micelle (PM) system composed of plasmid DNA (pDNA) and polyethylene glycol-<i>block</i>-poly-l-lysine copolymer (PEG-<i>b</i>-PLL), serving as a chromatin-inspired model, through chemical acetylation of PLL ε-amino groups. Unlike conventional polyplex systems that simply reproduce DNA condensation, this system enables controlled structural transitions from condensation to relaxation and activation of transcription, thereby reproducing a key epigenetic mechanism: acetylation-induced chromatin activation. Mechanistically, this process constitutes a cascade of reactions initiated by local electrostatic modulation through acetylation, which reduces PLL charge density, weakens electrostatic interactions with DNA, induces structural transitions, facilitates transcription factor association and implement mRNA synthesis, highlighting hierarchical control as a physicochemical principle that may underlie transcriptional regulation.