High‐Performance Multi‐Dynamic Bond Cross‐Linked Hydrogel with Spatiotemporal siRNA Delivery for Gene–Cell Combination Therapy of Intervertebral Disc Degeneration

Abstract Chronic inflammatory diseases, such as intervertebral disc degeneration (IVDD), which affect the lives of hundreds of millions of people, still lack effective and precise treatments. In this study, a novel hydrogel system with many extraordinary properties is developed for gene–cell combination therapy of IVDD. Phenylboronic acid‐modified G5 PAMAM (G5‐PBA) is first synthesized, and therapeutic siRNA silencing the expression of P65 mixed with G5‐PBA (siRNA@G5‐PBA) is then embedded into the hydrogel (siRNA@G5‐PBA@Gel) based on multi‐dynamic bonds including acyl hydrazone bonds, imine linkage, π – π stacking, and hydrogen bonding interactions. Local and acidic inflammatory microenvironment‐responsive gene‐drug release can achieve spatiotemporal regulation of gene expression. In addition, gene‐drug 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‐PBA@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–cell combination therapy and a precise and minimally invasive treatment method for IVD regeneration.