Heterofunctional Cationic Polyester Dendrimers as Potent Nonviral Vectors for siRNA Delivery

<b>Background/Objectives</b>: Heterofunctional cationic polyester dendrimers derived from a 2-(bromomethyl)-2-(hydroxymethyl)propane-1,3-diol (BHP-diol) based AB₂C monomer were evaluated as efficient and biodegradable nonviral carriers for siRNA delivery. <b>Methods</b>: These dendrimers feature dual internal and external charge architectures, enabling precise control of charge distribution and siRNA interaction strength. <b>Results</b>: They achieved complete siRNA complexation at nitrogen-to-phosphate (N/P) ratios of 0.50-2.14 and provided up to 93% RNase protection, outperforming amino-functional scaffolds based on 2,2-bis(methylol)propionic acid (bis-MPA). In human (T98G) and murine (GL261) glioblastoma cells, the dendrimers exhibited minimal cytotoxicity while achieving 52-61% target protein knockdown, a two- to three-fold improvement over conventional polyester dendrimers, and approaching the silencing efficiency of the commercial Interferin^® reagent. <b>Conclusions</b>: The combination of high complexation efficiency, strong nuclease resistance, and excellent biocompatibility establishes these heterofunctional dendrimers as a new generation of precisely tunable, biodegradable vectors for therapeutic siRNA delivery.