Nanoparticles are finding increased uses in drug delivery applications as a means to increase treatment efficacy and improve patient care. Here, we report engineered polymeric nanoparticles that undergo a hydrophobic to hydrophilic transition at pH 5 to afford swelling and rapid release of their contents. As our clinical interest ties in the prevention of lung tumor recurrence following resection, the nanoparticles were evaluated in a model mimicking microscopic disease, akin to residual occult tumor that can remain at the resection margin following surgery. Expansile nanoparticles loaded with paclitaxel, a poorly water-soluble anticancer drug, prevent establishment of lung cancer in vivo and are superior to the conventional drug delivery method for paclitaxel using Cremophor EL/ethanol.