Functional Dendrimer Nanogels for DNA Delivery and Gene Therapy of Tumors.

Solving the dilemma between efficacy and cytotoxicity of cationic colloidal vectors is one of the biggest challenges in gene delivery. Cationic dendrimer assemblies with hierarchical structure, smart and biomimetic behaviors have been developed for drug/gene delivery in vivo. Among different dendrimer assemblies, the dendrimer-based nanogels were not intensively studied due to complicated synthesis and unknown properties. Here, for the first time, low-generation dendrimer nanogels with high yield and purity, tunable size, uniform morphology, and good colloidal stability were synthesized using the emulsion-free method, which cannot be obtained by the miniemulsion method. Importantly, the dendrimer nanogels integrate the advantages of low-generation dendrimer and stimuli-responsive polymer, thus achieving dual-active groups, o-hydroxyl amine units, temperature-responsiveness, polyampholyte property, and self-triggered aminolysis. With these unique properties, dendrimer nanogels can "temporarily" acquire high charge density through the covalent crosslinking of low-generation dendrimer for improved DNA compression, promoted cell internalization and lysosomal escape, and efficient DNA delivery, followed by self-triggered aminolysis into small dendrimers to control DNA release, reduce cytotoxicity, and facilitate metabolism in vivo. Compared to high-generation dendrimers, low-generation dendrimer nanogels display higher gene transfection and therapeutic efficacies, and lower side effects simultaneously. This work provides a facile strategy for the preparation of low-generation dendrimer nanogels that break up the contradiction between efficacy and cytotoxicity of cationic colloidal vectors in gene therapy. This innovative approach to construct low-generation dendrimers into smart dendrimer nanogels will have broad applicability in clinical translation.