The synergistic efficacy and clinical application of light-responsive polymeric co-delivery systems are severely restricted by uncontrollable/imprecise drug loading, release, and adverse effects caused by the introduction of additional light-responsive molecules or contrast agents when diagnostic imaging is applied to guide therapy. Here, we report the design of a light-activatable dual prodrug polymer nanoparticle (DPP NP) for precise synergistic chemotherapy guided by drug-mediated computed tomography (DMCT) imaging without the introduction of any additional diagnostic imaging agent. DPP NP enables visible light-triggered prodrug polymer backbone cleavage and bioactive Pt(II) release in cancer cell/tumor site; the light-cleaved polymer fragments are further hydrolyzed to produce demethyl cantharidin (DMC). Notably, the drug loading ratio of Pt(IV) and DMC in DPP NP was fixed at an optimal value to achieve maximum synergistic cancer cell killing, which was kept even after cellular uptake, thereby resulting in enhanced synergistic antitumor efficacy both in vitro and in vivo. Because of the high content of the heavy metal Pt in the polymer chain, the spatial/temporal dynamic biodistribution as well as metabolism of DPP NP in vivo can be monitored by Pt DMCT imaging to guide the light irradiation parameters for optimized light-activatable synergistic chemotherapy. Guided by Pt DMCT imaging, DPP NP was able to achieve an improved light-activatable antitumor efficacy, with 75% tumors fully cured and low toxicity. The light-activatable DDP NP system exhibits tremendous potential as precise theranostic nanomedicine. STATEMENT OF SIGNIFICANCE: The synergistic efficacy and clinical application of light-responsive polymeric co-delivery systems are severely restricted by uncontrollable/imprecise drug loading, delivery, and release, as well as adverse effects caused by the introduction of additional light-responsive molecules or contrast agents when diagnostic imaging is applied to guide therapy. Herein, we report the design of a light-activatable dual prodrug polymer nanoparticle (DPP NP) for precise synergistic chemotherapy guided by drug-mediated computed tomography imaging without the introduction of any additional diagnostic imaging agents. Notably, the drug loading ratio of Pt(II) and DMC in DPP NP was fixed at an optimal value to achieve maximum synergistic cancer cell killing, which was kept even after cellular uptake, thereby resulting in enhanced synergistic antitumor efficacy both in vitro and in vivo. The light-activatable DDP NP system exhibits tremendous potential as precise theranostic nanomedicine.