1. Injectable self-healing hydrogel with siRNA delivery property for sustained STING silencing and enhanced therapy of intervertebral disc degeneration
- Author
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Haifeng Zhu, Linjun Yang, Zhi-Jun Hu, Jiaxin Chen, Chenchen Zhao, Ziang Xie, Yutao Zhu, Jia-Yong Dai, Yang Jin, Jin Zhang, Shengyu Wang, Honghai Song, Yixin Zheng, and Huaiyu Wang
- Subjects
musculoskeletal diseases ,siRNA delivery ,QH301-705.5 ,Biomedical Engineering ,Degeneration (medical) ,Gene delivery ,Article ,Biomaterials ,Extracellular matrix ,chemistry.chemical_compound ,Hyaluronic acid ,Gene silencing ,Biology (General) ,Materials of engineering and construction. Mechanics of materials ,Injectable hydrogel ,Gene knockdown ,Transfection ,musculoskeletal system ,IVD degeneration ,Cell biology ,Sting ,chemistry ,TA401-492 ,Dynamic Schiff base ,STING ,Biotechnology - Abstract
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., Graphical abstract Image 1, Highlights • STING-NF-κB pathway activation was identified an important cause of intervertebral disc degeneration. • PAMAM was employed as both linker and gene vector for siRNA delivery. • The injectable self-healing hydrogel could significantly ease the IVD inflammation and degeneration by prolonging STING knockdown. • This novel hydrogel system opened new ways of thinking and had great potential for gene delivery.
- Published
- 2022
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