A thermo-sensitive hydrogel targeting macrophage reprogramming for sustained osteoarthritis pain relief
Yue Liu, Kai Zhou, Xinlong He, Kun Shi, Danrong Hu, Chen Yang, Jinrong Peng, Yuqi He, Guoyan Zhao, Yi Kang, Yujun Zhang, Yue'e Dai, Min Zeng, Feier Xian, Wensheng Zhang, Zhiyong Qian
Abstract
Osteoarthritis (OA) causes chronic pain that significantly impairs quality of life, with current treatments often proving insufficient and accompanied by adverse effects. Recent research has identified the dorsal root ganglion (DRG) and its resident macrophages as crucial mediators of chronic OA pain through neuroinflammation driven by macrophage polarization. We present a novel injectable thermo-sensitive hydrogel system, KAF@PLEL, designed to deliver an anti-inflammatory peptide (KAF) specifically to the DRG. This biodegradable hydrogel enables sustained KAF release, promoting the reprogramming of DRG macrophages from pro-inflammatory to anti-inflammatory phenotypes. Through comprehensive in vitro and in vivo studies, we evaluated the hydrogel's biocompatibility, effects on macrophage polarization, and therapeutic efficacy in chronic OA pain management. The system demonstrated significant capabilities in preserving macrophage mitochondrial function, suppressing neuroinflammation, alleviating chronic OA pain, reducing cartilage degradation, and improving motor function in OA rat models. The sustained-release properties of KAF@PLEL enabled prolonged therapeutic effects while minimizing systemic exposure and side effects. These findings suggest that KAF@PLEL represents a promising therapeutic approach for improving outcomes in OA patients through targeted, sustained treatment. KAF@PLEL, a thermo-sensitive hydrogel for sustained delivery of the anti-inflammatory peptide KAF to the dorsal root ganglion (DRG), can reprogram macrophages, reduce neuroinflammation and cartilage degradation, and provide prolonged pain relief in osteoarthritis.