Herein, a doxorubicin-loaded carbon-based drug delivery system, denoted as PC-DOX, composed of pH-responsive imine bond was developed for the tumor-targeted treatment. PC-DOX with a uniform particle size around 180 nm was synthesized by coating of as-synthesized hollow carbon-based nanoparticles (NPs) with dialdehyde PEG, which was used as carrier to attach DOX covalently through dynamic covalent bond. The unique structure endowed the advantages of specific tumor targeting and tumor microenvironment (TME) specific drug delivery capacity with PC-DOX. For the one hand, the tumor targeting caused by the enhanced permeability and retention (EPR) effect could significantly improve the tumor cellular uptake. For the other hand, the pH-responsiveness could realize the effective DOX accumulation in tumor tissues, avoiding the unwanted side effect to the normal tissues. As a result, PC-DOX with high DOX loading capacity (70.12%) and excellent biocompatibility, concurrently, presented a significant anti-tumor effect at a low mass concentration (DOX equivalent dose: 20 μg/mL). Another attractive characteristic of PC-DOX was the remarkable protective effect towards DOX-induced cardiotoxicity, which could be clearly observed from in vitro cellular, and animal assays. Compared with free DOX, the cardiomyocyte viability increased by average 30.58%, and the heart function was also significantly improved. This novel drug delivery nanoplatform provides a new method for the future clinical application of DOX in the cancer’s therapeutics.