Aqueous binary dispersions of small soft and large hard colloidal spheres can provide an environmentally friendly vehicle for forming mechanically tough, crack-free latex films when the blend microstructure is tuned to avoid hard-particle percolation during drying. Recent work by Lewis and colleagues [V. Tohver et al., Langmuir 17 (26), 8414 (2001)] exemplifies one applicable microstructure, where highly charged nanoparticles group into adsorbed layers around nearly-neutral microspheres and cause an unusual phase behavior. We employ Monte Carlo simulations and evaluate rigorous virial expansions first to explicate the equilibrium adsorption and then to study the distribution of nanoparticles in the gap between two approaching microspheres. The latter yields the potential of mean force between the microspheres due to the interactions with the nanoparticles and permits estimates of the phase behavior and mechanical properties of the dispersions. The mechanism responsible in the microsphere-nanoparticle system provides guidance for formulation of blends with less drastic size asymmetry while retaining similar microstructure. We follow up with experimental studies that determine compatibility of such blends and test their potential for forming uniform films with desirable mechanical properties.