Impact of Stimuli-Responsiveness on the mRNA Delivery Efficiency of Low-Generation Dendrimer Nanogels

Development of efficient and stimuli-responsive gene delivery systems for therapeutic protein expression and immunomodulation remains challenging. Here, we report the synthesis of three types of pH-, reactive oxygen species (ROS)- and glutathione (GSH)-responsive dendrimer nanogels (for short, DNGs-pH, DNGs-ROS, and DNGs-GSH, respectively) via a microemulsion method for delivery of messenger RNA (mRNA) and plasmid DNA (pDNA), both encoding enhanced green fluorescent protein (for short, mEGFP and pEGFP), to dendritic cells (DCs). The synthesized DNGs exhibit a nanoscale dimension, high monodispersity, desired colloidal stability, low cytotoxicity, and efficient gene delivery efficiency. Importantly, the DNG-pH/mEGFP polyplexes exhibit a superior transfection performance to DCs, achieving 3.6-fold and 1.2-fold higher EGFP expression than the DNG-GSH/mEGFP and DNG-ROS/mEGFP, likely attributable to the synergistic proton sponge-mediated endosomal escape and pH-responsive dissociation of the DNGs. The developed pH-responsive DNGs could be an important candidate for highly efficient gene delivery to DCs for immune modulation.