A facile approach was established to fabricate the pH-responsive surface charge reversal carboxymethyl chitosan-based drug delivery system for pH and reduction dual-responsive triggered DOX release, with a reduction responsive sheddable shell via facile organic solvent-free co-precipitation method. In the proposed DDS, DOX was loaded in the pH responsive core of the poly(2-(diisopropylamino)ethyl methacrylate) (PDPA) fragments, which were bioreducibly conjugated onto the PEGylated carboxymethyl chitosan (PEG-CMCS) backbone as reduction responsive sheddable shielding shell. The proposed PEG-CMCS-SS-PDPA/DOX nanoparticles, with a high drug loading capacity of >36 % with drug-loading only in their cores, showed excellent pH and reduction dual-responsive triggered disintegration and DOX release performance with cumulative release >85 % in the simulated tumor intracellular microenvironment but a low drug leakage <8.5 % in the simulated normal physiological medium within 57 h, lower than all the reported CMCS-based DDSs.
