Diblock copolymer-based prodrugs have been widely designed for tumor treatment after self-assembly; however, premature drug leakage could not be ignored because their hydrophobic prodrug cores were directly exposed to the media. Here, an amphiphilic triblock copolymer prodrug with a hydrophilic PEG block, a pH-sensitive poly(2-(diisopropylamino)ethyl methacrylate) (PDPA) block, and a hydrophobic reduction-cleavable prodrug block was synthesized for tumor-specific pH/reduction dual-triggered drug delivery, via the successive RAFT polymerization of DPA and a DOX-based monomer (MAL-DOX) with a PEG-based macro-CTA. The core-shell and core-shell-corona nanoparticles could be obtained by one-step and two-step self-assembly. With the pH-sensitive gatekeeper formed by the PDPA block, the core-shell-corona nanoparticles possessed a smaller diameter with narrow distribution and better drug release with lower drug leakage. MTT assays demonstrated the selective cytotoxicity of the core-shell-corona nanoparticles to the cancer cells was dose-dependent because of the reduction-cleavable prodrug. The negligible drug leakage and selective cytotoxicity to cancer cells endow the proposed core-shell-corona prodrug nanoparticles with promising potential for tumor treatment without toxic side effects on the normal cells.