Premature drug leakage from the drug delivery systems (DDSs) causes severe toxic side effects on the normal cells, restricting their practical application in tumor chemotherapy. Here, core-crosslinked polyprodrug nanoparticles were designed by facile crosslinking-induced self-assembly of polyethylene glycol-b-poly(p-formylphenyl methacrylate) (PEG-PFPMA) di-block copolymer via acid-labile Schiff base bonds, with a pH-responsive doxorubicin-doxorubicin dimer (Di-DOX-ADH) as crosslinker. Owing to the unique structure, the chemotherapeutic drug, doxorubicin (DOX), could be released only when the Schiff base bond and hydrazone bond on both sides of the DOX unit were cleaved. Thus, a leakage-free tumor intracellular acid-triggered on-demand drug release was achieved with cumulative DOX release of 80 % in the simulated tumor intracellular microenvironment in 80 h. The proposed core-crosslinked polyprodrug nanoparticles could be internalized by the HepG2 cells and released DOX therein, exhibiting an enhanced tumor growth inhibition than free DOX.