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A nucleus penetrating vehicle is indispensible when seeking to deliver plasmid DNA for gene transfection. In this study, dendrimers with terminal thymine groups were synthesized to meet this objective. Through modifications of the hydrophilic and neutral thymine moieties on hyperbranched peripheries, these dendrimers can achieve biosafety, efficient endosomal escape ability, cytosolic accessibility, and eventually, nuclear entry for the purposes of gene transfection. After optimization of the thymine coverages, better gene expression can only be achieved while replacing ∼50% of the amine groups of a dendrimer with thymine moieties. Presumably, a specific dendrimer comprising thymine and primary amines might possess a synergistic effect to promote pDNA condensation via the cooperation of electrostatic interaction and hydrogen bonding. In comparison, a dendrimer entirely capped by thymine can lose external amines, decreasing pDNA complexity and stability, which would cause poor gene transfection. The utility of specific thymine-capped dendrimers in vivo level was demonstrated to successfully and efficiently deliver plasmid DNA at a low complex ratio into mouse muscle by intramuscular injection. Upon the easy accessibility of intramuscular administration, the capability of thymine-capped dendrimers might be potentially used in immunotherapeutic gene transfection in the future. [ABSTRACT FROM AUTHOR]

Nonviral vectors used in gene delivery, such as cationic polymers and dendrimers, exhibit problems of inherent toxicity and inefficient cytosolic access that must be overcome. In this work, a simple co-caging strategy focused on overcoming the two limitations of dendrimers for siRNA transfection is reported. By embedding gold nanoclusters within a dendrimer, the structure of the dendrimer becomes compact and allows an irreversible backfolding of exterior primary amines from the branch to the core, which dramatically eliminates dendrimer toxicity and enhances safety. Gold nanoclusters with strong emissions can confer a trackable function to dendrimers acting as a transfection vector (TV) for siRNA transfection. In order to maximize efficiency of complexing with siRNA, the TV further incorporated caged methyl motifs, transforming the partially tertiary amines into quaternary ammonium ions to form a methylated TV (MTV). The cellular responses to the MTV were similar to those of the TV, but the responses to the MTV can also enhance cytosolic access to better deliver siRNA for mRNA knockdown. This finding offers a novel perspective to facilitate the use of various cationic polymers for detoxification in biological applications through a co-caging strategy without further chemical modifications.