The intracellular activity and drug depot characteristics of micrometer-sized hydrogels are described. The hydrogel structure is formed after cellular uptake of a solid polymeric nanoparticle that swells in response to mildly acidic conditions as it transforms from a hydrophobic to a hydrophilic structure. These nanoparticles are rapidly taken up into A549 human non-small cell lung cancer cells with 88.3 ± 0.8% of cells experiencing uptake in 24 h, undergo expansion to release encapsulated drug and can effectively deliver chemotherapeutics in vitro. The anticancer drug paclitaxel was also shown to have a 3- to 4-fold increased affinity for the expanded nanoparticle state, allowing the expansile nanoparticles to act as intracellular drug depots and concentrate the drug locally.