pH/redox-responsive release of interleukin-4 from ZIF-8@diselenide block copolymer to regulate inflammation

•A polymer with diselenide bonds was applied as a shell on IL-4@ZIF-8@SHP.•IL-4 delivery system was obtained with stepwise pH and redox responsive release.•This targeted release alleviated IL-4 side effects in normal tissues.•IL-4@ZIF-8@SHP modulated the temporal polarization of macrophages from M1 to M2. Multi-responsive drug-delivery systems have been widely explored to enable specific delivery to target sites. Here, interleukin-4 (IL-4), an anti-inflammatory cytokine, is first encapsulated in situ inside a zeolitic imidazolate framework (ZIF-8) to form IL-4@ZIF-8, which is subsequently coated with a diselenide block copolymer to obtain IL-4@ZIF-8@Se-Se-polymer. This delivery system enables redox-responsive release of IL-4 by the diselenide copolymer and a pH-triggered release by ZIF-8. Moreover, IL-4 release is precisely controlled stepwise by the stimuli response, with the dissociation of the diselenide copolymer, and breakdown of the ZIF-8 structure. The targeted release property of the IL-4@ZIF-8@Se-Se-polymer endows the materials with efficient macrophage immune regulation, as systematically demonstrated in vitro. This study provides an effective example of the delivery and on-demand release of IL-4, and may find promising applications in tissue engineering for the management of inflammation.