Herein, a kind of multi-responsive core-crosslinked poly (thiolether ester) micelles was facilely prepared for reactive oxygen species (ROS), acid and reduction sensitive drug delivery. Firstly, a hydroxyl-rich poly (thiolether ester) (PTE) was synthesized by the thiol-ene/thiol-expoxy polymerization using ethanedithiol (EDT) and glycidylmethacrylate (GMA) as monomers. The resultant PTE was then coupled with carboxyl terminated poly (ethylene glycol) (PEG) and lipoic acid (LA) to give the graft copolymer PTE-g-PEG-LA. The obtained PTE-g-PEG-LA could self-assemble into micelles in the aqueous media and turn into core-crosslinked nanoparticles in the presence of dithiothreitol (DTT) at pH similar to 8.3.The core-crosslinked PTE-g-PEG-LA micelles showed more compact structure and higher drug loading efficiency towards the model drug doxorubicin (DOX) as compared with non-crosslinked PTE-g-PEG micelles. In vitro drug release profiles demonstrated that the release of drug from DOX-loaded core-crosslinked PTE-g-PEG-LA micelles (CNP/DOX) could be accelerated in the ROS-abundant, acidic or reductive environment. The triggered release of loading drug from CNP/DOX in A549 and HeLa cells were also verified by laser scanning confocal microscopy, flow cytometry and cell proliferation inhibition assessments. These results indicate that the cross-linked PTE-g-PEG-LA micelles may provide huge potential for smart drug delivery in cancer therapy. (C) 2017 Elsevier Ltd. All rights reserved.