Systems and methods for targeting specific cancer cell subpopulations present in tumor tissue are described. A system can include a first component for specifically targeting cancer stem cells and a second component for specifically targeting differentiated cancer cells. A system can include a drug conjugated to small (e.g., 5-20 nm) nanoparticles, e.g., polyhedral oligomeric silsequioxane nanoparticles. The small nanoparticles can be preferentially taken up by cancer stem cells via macropinocytosis and can release a toxic payload within the cancer stem cells without triggering the efflux pump. A system can include a second component that targets differentiated cancer cells, e.g., a free drug or a drug encapsulated in nanoparticles.