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@HP^gel) 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@HP^gel 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.

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.

Elevated oxidative stress and inflammation, bacterial infections, and vascular impairment undoubtedly impede the normal diabetic wound healing process, which has encouraged the development of high-performance dressings for wound management. Herein, a new type of multiple-crosslinked injectable hydrogel, GCP, was developed via the radical polymerization of propenyl groups and the formation of copper‒polyphenol coordination bonds and Schiff base bonds. The copper‒polyphenol coordination and Schiff base bonds in the GCP hydrogel were disrupted in the acidic microenvironment of diabetic wound, resulting in the release of copper ions and protocatechualdehyde (PA) to scavenge reactive oxygen species (ROS), promote angiogenesis and cell migration, and exert antibacterial and anti-inflammatory activities via the CuPA complexes. Consequently, markedly accelerated infected diabetic wounds healing was achieved through this tissue microenvironment remodeling strategy. Moreover, the underlying mechanism of the antibacterial properties was investigated by 16S rRNA sequencing. The results indicated that the CuPA complexes can clearly inhibit the growth and reproduction of S. aureus by downregulating specific genes associated with ABC transporters, hindering bacterial protein synthesis, and enhancing oxidoreductase activity. This innovative hydrogel platform for wound management may inspire new methods for the preparation of high-performance biomedical materials and the treatment of other clinical diseases.