An "all-in-one" therapeutic platform for programmed antibiosis, immunoregulation and neuroangiogenesis to accelerate diabetic wound healing.

Abstract

Pathological microenvironment of diabetes induces a high risk of bacterial invasion, aggressive inflammatory response, and hindered neuroangiogenesis, leading to retarded ulcer healing. To address this, an "all-in-one" therapeutic platform, named MZZ, was constructed by loading maltodextrin onto a MOF-on-MOF structure (with ZIF-67 as the core and ZIF-8 as the shell) through a hybrid process of solvent treatment and electrostatic adsorption. Maltodextrin acts as a target to bind surrounding bacteria, and ZIF-8 as well as ZIF-67 responsively release Zn and Co ions, which not only kill most bacteria, but also improve the phagocytosis and xenophagy of M1 macrophages by up-regulating the expression levels of ATG5, Bcl1 and FLT4, helping the residual bacterial clearance. In inflammatory stage, MZZ scavenges extracellular and intracellular ROS by valence transition between Co²⁺ and Co³⁺, and promote M1 macrophages to transform into M2 phenotype. In tissue reconstruction stage, the synergistic effect of Zn and Co ions as well as cytokines secreted by macrophages up-regulates cell vitality and biofunctions of endotheliocytes, neurocytes and fibroblasts. The programmed effects of MZZ on antibiosis, anti-inflammatory and neuroangiogenesis to accelerate wound repair are further confirmed in an infected diabetic model, and this "all-in-one" platform shows great clinical application potential.