Self‐Amplification Immunomodulatory Strategy for Tissue Regeneration in Diabetes Based on Cytokine‐ZIFs System

Abstract Dysfunctional macrophages and excessive inflammatory responses lead to severe tissue regeneration disorders in diabetes. Herein, a function‐oriented self‐amplification immunomodulatory (SAI) strategy based on an interleukin‐33 (IL‐33) loaded zeolitic imidazolate frameworks (IL@ZIF) nano‐platform is proposed to treat tissue regeneration disorders by restoring macrophage function and reconstructing immune microenvironment in diabetes. It is found that ZIFs effectively protect IL‐33 from premature degradation. In the wound area, the released Zn 2+ not only improves the antioxidant capacity of macrophages to avoid reactive oxygen species‐induced dysfunction, but also upregulates IL‐33 receptor (ST2L) expression and triggers M2 macrophages polarization. Subsequently, the released IL‐33 significantly amplifies M2 macrophage polarization through IL‐33/ST2L signaling, resulting in a reversal of the pro‐inflammatory microenvironment of diabetic wounds. This synergistic effect endows the nano‐platform with an excellent ability to accelerate tissue regeneration in vitro and in vivo. Overall, this IL@ZIF mediated function‐oriented SAI strategy provides new alternatives for the treatment of tissue regeneration disorders in diabetes.