Hydrogels Targeting Mechanical–biological signaling transitions of interleukin-33 alleviates intervertebral-disc degeneration

Mechanical-biological signaling transitions (MBSTs) cause intervertebral-disc degeneration (IVDD). The key to MBSTs lies in nucleus pulposus cells (NPCs), but it is not yet fully understood, and relevant therapeutic targets and strategies are lacking. In this study, we found that the key mechanobiological-signaling factor interleukin-33 (IL-33) played an important role in stress-induced IVDD through a piezo-type mechanosensitive ion channel component 1 (PIEZO1)-mediated positive-feedback loop. Specifically, analysis of clinical samples showed that IL-33 was significantly upregulated in NPCs from IVDD patients and that compressive-stress stimulation further enhanced IL-33 expression via the PIEZO1 pathway, thereby accelerating disc degeneration. To discover the underlying mechanism, we fabricated the transfection nanoparticles formed by benzoboric acid-modified polyethyleneimine (PEI-PBA) with <i>Il-33</i> small-interfering ribonucleic acid (siRNA) and encapsulated them in gelatin methacrylate (GelMA) hydrogel microspheres for enhanced IVDD gene therapy. The functinalized PEI significantly improved the transfection efficiency of <i>Il-33</i> siRNA. Meanwhile, the GelMA hydrogel microspheres (GMs) showed excellent Matrix Metalloroteinase (MMP) response properties, which might regulate the IVDD microenvironment to improve the effect of gene therapy. The gene GMs delivery system for targeted IL-33 therapy not only showed good therapeutic effect on IVDD but also provided more ideas for future translational-medicine research.