Recently, the global trend in the field of nanomedicine has been toward the design of highly sophisticated drug delivery systems with specific targeting and synergistic therapeutic functions for improving therapeutic efficacy. But offering sophistication generally increases their complexity that might be disadvantageous in pharmaceutical development. We hypothesize that using a macromolecular prodrug with a dual role will be conductive to integrating its dual function into self-targeted multidrug co-delivery and combination cancer therapy. In this paper, the on-off switching function-responsive, macromolecular methotrexate (MTX) prodrug-self-targeted, controlled-/sustained-release, and high drug-loading hydroxylcamptothecin (HCPT) drug nanospheres were prepared and characterized. The self-targeting system can co-deliver multi-drug to different action sites with distinct anticancer mechanisms to specifically target folate receptors-overexpressing cancer cells with synergistic therapeutic efficiency.