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) in vitro 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 in vitro and in vivo, 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.