Controlled releasing melatonin nanoparticles promote restoration of nucleus pulposus cell homeostasis for alleviating intervertebral disc degeneration

The intervertebral administration of anti-inflammatory drugs is a promising local delivery approach to the intervertebral disc integrity restoration for treatment of intervertebral disc degeneration (IVDD), whereas the fast drug clearance in an intervertebral space is always a troublesome issue for the local drug delivery. In this study, we have developed a zeolitic imidazolate framework 8 (ZIF-8) nanoplatform with pH-sensitive property to load melatonin molecules (MT), a hormone with anti-inflammatory and anti-oxidative effects. Thus-synthesized MT@ZIF-8 nanoparticles not only showed good cytocompatibility and pH-dependent drug releasing behavior, but also effectively decreased the intracellular reactive oxygen species level and inhibited the pro-inflammatory cytokine expression for <i>in vitro</i> nucleus pulposus cell (NPC) culture under lipopolysaccharide (LPS) stimulus. Additionally, it was found that NF-κB and MAPK signal pathways are significantly suppressed by the MT@ZIF-8 nanoparticles for the LPS-treated NPCs, revealing the underlying mechanism of restoring extracellular matrix synthesis of the LPS-treated NPCs by the MT@ZIF-8 nanoparticles. Last but not least, the recovery of intervertebral disc components and integrity were observed on a rat caudal IVDD model after injection of the MT@ZIF-8 nanoparticles into the intervertebral space. In brief, this work offered a promising local delivery strategy and a controlled releasing nanoplatform for the applications of melatonin in the IVDD therapy, which we think may have beneficial effects for future clinical treatment of low back pain caused by the IVDD.