Rational charge engineering in nanogels for enhanced siRNA delivery

Cationic nanogels have emerged as promising siRNA delivery vectors, yet the design principles of their charge motifs for potent delivery remain elusive. Here, we develop a reduction-responsive cationic nanogel incorporating both quaternary ammonium and tertiary amino groups. Rational charge optimization enhances siRNA loading, cellular uptake, and endosomal escape, achieving remarkable gene silencing superior to that of commercial Lipofectamine 3000. Our findings demonstrate charge engineering as a viable strategy toward the rational design of efficient polymeric vectors for nucleic acid therapeutics.