A fluorinated Janus-type dendrimer as an ionizable one-component nanocarrier for nucleic acids

Abstract

Gene therapies based on nucleic acids (NAs) represent a new class of emerging drugs for the cure and prevention of several pathologies. NAs encounter significant challenges in intracellular uptake due to enzymatic degradation and their negative charge, which hinders membrane crossing. Specialized delivery carriers are used to allow NAs’ cellular internalization and release in the cytosol for effective biological function. Among non-viral vectors, dendrimers have emerged as promising candidates, but the high costs of synthesizing high-generation dendrimers may limit their clinical use. Supramolecular dendrimers can be a compelling alternative. In this context, we developed a 2nd-generation Fluorinated Janus-type dendrimer (FJD₂N) accurately designed to feature a robust, ¹⁹F-MRI-traceable hydrophobic self-assembling moiety, an optimal balance between fluorinated and hydrophilic groups, and an appropriate number of protonable primary amines. We showed that the designed dendrimer can effectively form dendriplexes with the NAs and safely transport them into different cell types, with successful transfection efficacies and low cytotoxic effects.