The event of a controllable reactive nitrogen species (RNS) era system for most cancers therapy has remained elusive. Herein, a supramolecular prodrug nanoassemblies (SPNA) technique that co-delivers a nitric oxide (NO) donor and a superoxide anion (O2•–) inducing chemotherapeutic agent was reported for RNS-potentiated chemotherapy. The mole ratio of platinum(IV) prodrug and NO donor might be exactly tailor-made in SPNAPt/NO. Platinum(II) and NO could be launched intracellularly to provide a extremely poisonous RNS, peroxynitrite anion (ONOO–). The degrees of glutathione reductase (GR) and xeroderma pigmentosum group A (XPA) have been down-regulated by ONOO–, thus synergistically lowering detoxing and blocking DNA harm restore of Pt-based chemotherapy. The RNS-potentiated efficacy of SPNAPt/NO was validated on subcutaneous hepatoma xenograft fashions and an orthotopic cisplatin-resistant hepatoma mannequin. This co-delivery technique of NO donor and O2•– inducing chemotherapeutic brokers for RNS-mediated remedy offers an insightful course for most cancers therapy.