Multi-target hydrogel therapy to disrupt the AGEs–RAGE–ROS cycle in chronic diabetic wound healing

• Injectable, self-healing hydrogel interrupts AGEs–RAGE–ROS cycle to restore diabetic wound microenvironment • MnO 2 @PCA–QCMC matrix provides antibacterial, ROS-scavenging, oxygenation, and pro-angiogenic actions. • In vitro/in vivo studies show accelerated healing, reduced inflammation, and enhanced collagen deposition. Chronic diabetic wounds (CDWs) are refractory lesions characterized by oxidative stress, persistent infection, inflammation, ischemia, and excessive advanced glycation end products (AGEs). Binding of AGEs to their receptor (RAGE) triggers inflammatory and oxidative pathways, reinforcing a vicious cycle that impedes healing. Here, we developed a multifunctional hydrogel by crosslinking aldehyde-rich MnO 2 @protocatechualdehyde (PCA) nanoparticles with quaternized carboxymethyl chitosan (QCMC) via a Schiff base reaction, incorporating molybdenum disulfide (MoS 2 ) quantum dots. This hydrogel exhibits antibacterial activity, scavenges reactive oxygen species (ROS), reduces AGEs and RAGE expression, alleviates hypoxia, and promotes angiogenesis. In vitro and in vivo experiments demonstrated that it effectively inhibits bacterial growth, mitigates inflammation, enhances neovascularization, and accelerates CDW healing. This work offers a promising strategy for multi-target regulation of diabetic wound microenvironments.