Novel anti-pyroptosis drug loaded on metal-organic framework for intervertebral disc degeneration therapy

Intervertebral disc degeneration (IVDD) is the main cause of low back pain, pyroptosis is a major contributor to various diseases, including IVDD; however, there is currently no effective drugs targeting pyroptosis for therapy. In this study, we established pyroptosis model in nucleus pulposus cells (NPCs) <i>in vitro</i> and searched pyroptosis inhibitors in FDA Medicine Library. High throughput screening study revealed that Pirfenidone (PFD) was the most effective pyroptosis inhibitor among 1500+ FDA drugs, which was confirmed by further experiments. As administering PFD alone may lead to poor efficacy due to short action time and low bioavailability, we designed a smart delivery system for PFD. A pH-responsive metal-organic framework (MOF), poly-His6-zinc (PHZ) assembly, loaded with PFD (PFD@PHZ) was designed for IVDD therapy. PHZ was shown to have excellent lysosomal escape properties and bioavailability of PFD. In addition, the release of PDF from PFD@PHZ could be triggered by the acidic microenvironment of degenerated intervertebral discs. PFD@PHZ was also shown to effectively inhibit pyroptosis, senescence, and extracellular matrix (ECM) degradation in NPCs, both <i>in vitro</i> and <i>in vivo</i>, thereby mitigating the progression of IVDD in rats. Thus, the current study shows PFD as a novel inhibitor for pyroptosis, and PFD@PHZ as a potential nanomaterial for efficient IVDD therapy.