The high cationic charge density of the polymers used in synthetic gene therapy vectors makes these systems toxic and induces non-specific interactions with blood components. Covalent modification of the positively charged terminal amines with hydroxyl, acetyl, poly(ethylene glycol) or methyl groups reduces not only the toxicity but also the condensation capacity, leading to lower transfection efficiency and changes in nanoparticle biodistribution. The colloidal properties of such nanoparticulate systems can be optimised based on the hydration forces active on their surface. Specifically, a core–shell strategy was used to optimise hydration forces and stabilise the vector system by separating vector functions into those provided by the core, where polypropylenimine dendrimers (DAB-Am16) mediate complexation and transfection functionality, and those linked to the shell, where a hyaluronic acid (HA) coat affords colloidal stability and systemic targeting. This core–shell vector allows a 6-fold reduction in the amount of cationic polymer used to form the nucleic acid core complex, compared to conventional nanoparticles. The HA shell was optimised in terms of thickness and density by maximising short-range hydration forces under physiological conditions. The resulting vector particles also allow specific targeting and transfection of CD44 positive cancer cells. The HA coated particles show reduced toxicity (2.5-fold) and increased transfection (8-fold) compared to the conventional dendriplex. In conclusion, we demonstrate a strategy for independent optimisation of vector core and shell functionality which allows specific targeting and increases the therapeutic index of the non-viral vector system 20-fold.