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In this study, a novel hydrogel system with many extraordinary properties is developed for gene\u2013cell combination therapy of IVDD. Phenylboronic acid\u2010modified G5 PAMAM (G5\u2010PBA) is first synthesized, and therapeutic siRNA silencing the expression of P65 mixed with G5\u2010PBA (siRNA@G5\u2010PBA) is then embedded into the hydrogel (siRNA@G5\u2010PBA@Gel) based on multi\u2010dynamic bonds including acyl hydrazone bonds, imine linkage, <jats:italic>\u03c0<\/jats:italic>\u2013<jats:italic>\u03c0<\/jats:italic> stacking, and hydrogen bonding interactions. Local and acidic inflammatory microenvironment\u2010responsive gene\u2010drug release can achieve spatiotemporal regulation of gene expression. In addition, gene\u2010drug release from the hydrogel can be sustained for more than 28 days in vitro and in vivo, greatly inhibiting the secretion of inflammatory factors and the subsequent degeneration of nucleus pulposus (NP) cells induced by lipopolysaccharide (LPS). Through prolonged inhibition of the P65\/NLRP3 signaling pathway, the siRNA@G5\u2010PBA@Gel is verified to relieve inflammatory storms, which can significantly enhance the regeneration of IVD when combined with cell therapy. Overall, this study proposes an innovative system for gene\u2013cell combination therapy and a precise and minimally invasive treatment method for IVD regeneration.<\/jats:p>","DOI":"10.1002\/advs.202206306","type":"journal-article","created":{"date-parts":[[2023,4,20]],"date-time":"2023-04-20T14:46:16Z","timestamp":1682001976000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":54,"title":["High\u2010Performance Multi\u2010Dynamic Bond Cross\u2010Linked Hydrogel with Spatiotemporal siRNA Delivery for Gene\u2013Cell Combination Therapy of Intervertebral Disc Degeneration"],"prefix":"10.1002","volume":"10","author":[{"given":"Jiaxin","family":"Chen","sequence":"first","affiliation":[{"name":"Center for Plastic &amp; Reconstructive Surgery Department of Plastic &amp; Reconstructive Surgery Zhejiang Provincial People's Hospital Affiliated People's Hospital Hangzhou Medical College  Hangzhou 310014 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haifeng","family":"Zhu","sequence":"additional","affiliation":[{"name":"Key Laboratory of Musculoskeletal System Degeneration Regeneration Translational Research of Zhejiang Province Department of Orthopaedic Surgery Sir Run Run Shaw Hospital Zhejiang University School of Medicine  Hangzhou 310016 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiechao","family":"Xia","sequence":"additional","affiliation":[{"name":"Key Laboratory of Musculoskeletal System Degeneration Regeneration Translational Research of Zhejiang Province Department of Orthopaedic Surgery Sir Run Run Shaw Hospital Zhejiang University School of Medicine  Hangzhou 310016 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yutao","family":"Zhu","sequence":"additional","affiliation":[{"name":"Key Laboratory of Musculoskeletal System Degeneration Regeneration Translational Research of Zhejiang Province Department of Orthopaedic Surgery Sir Run Run Shaw Hospital Zhejiang University School of Medicine  Hangzhou 310016 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chen","family":"Xia","sequence":"additional","affiliation":[{"name":"Department of Orthopedic Surgery Zhejiang Provincial People's Hospital Affiliated People's Hospital Hangzhou Medical College  Hangzhou 310014 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zehui","family":"Hu","sequence":"additional","affiliation":[{"name":"Key Laboratory of Musculoskeletal System Degeneration Regeneration Translational Research of Zhejiang Province Department of Orthopaedic Surgery Sir Run Run Shaw Hospital Zhejiang University School of Medicine  Hangzhou 310016 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang","family":"Jin","sequence":"additional","affiliation":[{"name":"Key Laboratory of Musculoskeletal System Degeneration Regeneration Translational Research of Zhejiang Province Department of Orthopaedic Surgery Sir Run Run Shaw Hospital Zhejiang University School of Medicine  Hangzhou 310016 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ji","family":"Wang","sequence":"additional","affiliation":[{"name":"Center for Plastic &amp; 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