To achieve an ideal drug delivery platform with precise composition and high tumor selectivity, the PEGylated dual-drug backboned prodrug was synthesized via the copolymerization between diamine monomer of ortho ester and cisplatin- demethylcantharidin conjugate (Pt(IV)-1), and then terminated by mPEG550-active ester. The amphipathic prodrug could self-assemble into nano-prodrugs, which endowed the precise structure and high drug loading. Moreover, the nano-prodrugs exhibited physicochemical stability at physiological pH (7.4) for stable blood circulation, DePEGylation and dynamic size change for selective tumor accumulation and enhanced cellular internalization at tumoral extracellular pH (6.8), and efficient drug release for synergetic apoptosis and cytotoxicity at tumoral intracellular pH (5.0)/glutathione. Thus, the precise dual-drug backboned nano-prodrugs with detachable PEGylation, dynamic size change and efficient drug release could be potentially translated for clinically selective cancer treatment. STATEMENT OF SIGNIFICANCE: Few nanomedicines have been clinically used for cancer treatment and little progress has been made in the last decades due to the unprecise composition and unsatisfactory tumor selectivity. Herein, the PEGylated dual-drug backboned nano-prodrugs were successfully constructed by rational design and endowed the defined structure, precise drug ratio, extraordinary high drug loading and reduction/pH dual sensitivity. The nano-prodrugs further exhibited the stable storage and blood circulation through PEGylation and low critical micelle concentration, enhanced tumor accumulation and cellular uptake via extracellular DePEGylation and dynamic size translation, and synergetic cytotoxicity via intracellular efficient drug release, respectively. This study can open a new avenue for easy industrial manufacture and quality control, and highly selective chemotherapy appealing for clinical translation. .