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

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@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.

Hydrogels for RNA delivery

“…pH-responsive release. pH-responsive hydrogels often contain Schiff base bonds, which are stable at pH 7.4 but disrupted in an acidic environment (for example, pH 6.8) 75 . Such hydrogels are suitable for on-demand release of RNA in diseases associated with an acidic tissue microenvironment (such as cancer and myocardial infarction (MI)).…”

“…Bone regeneration and repair is another arena in which hydrogelmediated RNA delivery has shown promise 72,75 . Bone healing relies on several dynamic and spatiotemporal mechanisms, including inflammatory, repair, and remodeling phases at crucial cellular (that is, inflammatory cells, vascular cells, osteochondral progenitors, and osteoclasts) and molecular levels (that is, pro-inflammatory cytokines, growth factors, and angiogenic and pro-osteogenic factors) 83 .…”

Functionalized PAMAM constructed nanosystems for biomacromolecule delivery

“…The hydrogel successfully delivered the gene to ease IVD inflammation and slow IVD degeneration in an IVD degeneration rat model. 174 For another example, PBA-modified G5 PAMAM was cross-linked with polyvinyl alcohol (PVA) to yield a hydrogel for anticancer agent delivery. After administration, the gene complex was released from the hydrogel steadily, then crossing the cell membrane and escaping from the endosome/lysosome, thereby improving in vivo gene therapeutic efficacy.…”

Spheroid-Based Tissue Engineering Strategies for Regeneration of the Intervertebral Disc

“…While not yet applied to spheroids, cell/growth factor-loaded particles ensured sustained release and chondrogenic differentiation of encapsulated therapeutic cells, aiding IVD regeneration in animal models [ 204 , 205 ]. Similarly, cell-free siRNA complexes encapsulated in injectable HA hydrogels retained release/activity over a prolonged period of time in vitro and in vivo [ 206 ]. Continuous supply of bioactive material combined with 3D cell configurations might enhance differentiation into chondrocyte-like NP cells as well as rejuvenate resident IVD tissue [ 204 ].…”