The instability and premature charge reversal at pH 7.4 have become the major limitations of charge-reversal delivery systems. To address this problem, graft copolymer of poly(butylene succinate)-g-cysteamine-bi-poly(ethylene glycol) (PBS-g-CS-bi-PEG, bi=benzoic imine bond) was designed and synthesized through facile thiol-ene click reaction and subsequent Schiff's base reaction. Then, PBS-g-CS-bi-PEG and carboxyl-functionalized polyester of poly(butylene succinate)-g-3-mercaptopropionic acid (PBS-g-MPA) co-assemble in aqueous solution to give PEG shell-sheddable charge-reversal micelles with sizes of 85-103 nm and low polydispersity of 0.11-0.12. Interestingly, the PBS-g-MPA/CS-bi-PEG micelles could sensitively and arbitrarily switch their surface charges between negative and positive status in response to pH fluctuation via reversible protonation and deprotonation of carboxyl and amino groups, which endows the desired stability of co-assembly micelles either during long-term storage or under physiological conditions. Doxorubicin (DOX) was loaded into PBS-g-MPA/CS-bi-PEG micelles with a high drug-loading content of 10.2% and entrapment efficiency of 68% as a result of electrostatic attraction. In vitro release studies revealed that less than 25% of DOX was released within 24 h in the environment mimicking the physiological condition, whereas up to 81% of DOX was released in 24 h under weak-acid condition resembling microenvironment in endosome/lysosome. In vitro cytotoxicity study suggested that blank PBS-g-MPA/CS-bi-PEG micelles possessed excellent biocompatibility, while DOX-loaded PBS-g-MPA/CS-bi-PEG micelles showed significant cytotoxicity with half-maximal inhibitory concentration (IC50) of 1.55-1.67 g DOX equiv/mL. This study provides a facile and effective approach for the preparation of novel charge-reversal micelles with switchable charges and excellent biocompatibility, which are highly promising to be used as safe nanocarriers for efficient intracellular drug delivery. (c) 2017 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2017, 55, 2036-2046