Multifunctional hydrogel loaded with 4-octyl itaconate and exosomes to induce bone regeneration for diabetic infected bone defect via Keap1-Nrf2 pathway

Diabetic infected bone defect remains a great challenge in clinical practice, with delayed healing characterized by bacterial infection and cellular disfunction caused by oxidative stress. Hence, a novel self-healing multifunctional Ag@PEG-4OI/EXO hydrogel is introduced for improving healing of diabetic infected bone defect. 4-octyl itaconate, a derivative of the metabolite itaconate, has been proved that which performs antioxidant and mitochondria-protected properties. Simultaneously, the Ag⁺ that performed as cross-linking agent binds 4-arm-PEG-SH to form anti-bacterial hydrogel to deliver the bioactive molecule. The released of 4OI is confirmed that it can alleviate excessive ROS damage to cells and protect mitochondrial functions according to Keap1-Nrf2 pathway, synergistically promoting neurovascularization and osteogenic differentiation with EXO (from repair Schwann cells). In vivo, the Ag@PEG-4OI/EXO hydrogel also shows ideal antibacterial property and ameliorate the microenvironment of cells, finally promoting regeneration of CGRP⁺ nerve fibers and bone healing. In vivo and in vitro studies demonstrate that the improvement functions of cells with the use of the Ag@PEG-4OI/EXO hydrogel, presenting a viable strategy for diabetic infected bone defect.