Injectable self-healing hydrogel with siRNA delivery property for sustained STING silencing and enhanced therapy of intervertebral disc degeneration  

作　　者：Jiaxin Chen Haifeng Zhu Yutao Zhu Chenchen Zhao Shengyu Wang Yixin Zheng Ziang Xie Yang Jin Honghai Song Linjun Yang Jin Zhang Jiayong Dai Zhijun Hu Huaiyu Wang 

机构地区：[1]Department of Orthopaedic Surgery,Sir Run Run Shaw Hospital,Zhejiang University School of Medicine,Key Laboratory of Musculoskeletal System Degeneration,Regeneration Translational Research of Zhejiang Province,East Qing Chun Road,Hangzhou,310016,PR China [2]College of Chemical Engineering,Fuzhou University,2 Xueyuan Road,Fuzhou,350108,PR China [3]Center for Human Tissues and Organs Degeneration,Shenzhen Institutes of Advanced Technology,Chinese Academy of Sciences,Shenzhen,518055,Guangdong,PR China

出　　处：《Bioactive Materials》2022年第3期29-43,共15页生物活性材料（英文）

基　　金：The study was sponsored by National Natural Science Foundation of China(81672150,51903050);Zhejiang medical and health science and technology project(2018KY117,2019ZD041);Natural Science Foundation of Zhejiang Province of China(LQ20H160053);New talent in medical field of Zhejiang Province,and the fundamental research funds for the central universities(2019QNA7027).

摘　　要：Inflammatory responses of nucleus pulposus(NP)can induce imbalanced anabolism and catabolism of extracellular matrix,and the cytosolic dsDNA accumulation and STING-NF-κB pathway activation found in NP inflammation are considered as fairly important cause of intervertebral disc(IVD)degeneration.Herein,we constructed a siSTING delivery hydrogel of aldehyde hyaluronic acid(HA-CHO)and poly(amidoamine)PAMAM/siRNA complex to intervene the abnormal STING signal for IVD degeneration treatment,where the formation of dynamic Schiff base bonds in the system(siSTING@HPgel)was able to overcome the shortcomings such as low cellular uptake,short half-life,and rapid degradation of siRNA-based strategy.PAMAM not only formed complexes with siRNA to promote siRNA transfection,but also served as dynamic crosslinker to construct hydrogel,and the injectable and self-healing hydrogel efficiently and steadily silenced STING expression in NP cells.Finally,the siSTING@HPgel significantly eased IVD inflammation and slowed IVD degeneration by prolonging STING knockdown in puncture-induced IVD degeneration rat model,revealing that STING pathway was a therapeutic target for IVD degeneration and such novel hydrogel had great potential for being applied to many other diseases for gene delivery.

关 键 词：STING IVD degeneration siRNA delivery Injectable hydrogel Dynamic Schiff base 

分 类 号：R318[医药卫生—生物医学工程] TB3[医药卫生—基础医学]