Mechanism of dendrimer-mediated siRNA delivery and TWIST1 knockdown. (1) Negatively charged siRNA is electrostatically attracted to positive charges on the YTZ3-15 dendrimer, leading to the formation of 6–8 nm diameter micelles coated with siRNA. (2) These dendriplexes are administered to tumor cells. (3) Dendriplexes are taken up via macropinocytosis. (4) Dendriplexes are trafficked to late endosomes. (5) Due to the proton sponge effect, electrostatic interactions between the dendrimer and siRNA are disrupted and siRNA escapes from the disrupted endosome into the cytosol. (6) Once in the cytosol, siRNA recruits the endogenous RNAi machinery to degrade TWIST1 mRNA. Following TWIST1 knockdown, TWIST1 target gene expression is altered to reduce invasive capacity.