Stem Cell Membrane-Camouflaged Biomimetic Nanoparticles Inhibiting Leptin Pathway for Intervertebral Disc Degeneration Therapy

Leptin, a kind of adipokine, with its receptor in which the long isoform plays a crucial role in signal transduction, has been identified in intervertebral disc (IVD) tissues, especially showing an increased expression in degenerated discs. Initially identified as a metabolic sensor, leptin has recently been found able to regulate inflammation into imbalance, which favors catabolic degradative processes, thus contributing to progressive intervertebral disc degeneration (IDD). Therefore, efficiently inhibiting the leptin pathway may provide a new strategy to treat IDD. In this study, we introduced an innovative drug delivery system (DDS) that employs stem cell membranes (SCM) to encapsulate (Zeolitic imidazolate frameworks-8) ZIF-8 nanoparticles. These nanoparticles are used to transport a plasmid containing shRNA targeting the leptin receptor (LEPR), with the aim of facilitating repair in IDD. The regenerative performances of this DDS in IDD were verified through a combination of the <i>in vitro</i> western blot and immunofluorescence with the <i>in vivo</i> radiologic examination and histological staining. The DDS demonstrated excellent cell adhesion properties and gene transfection efficiency <i>in vitro</i>, along with impressive treatment outcomes <i>in vivo</i>. Both <i>in vitro</i> and <i>in vivo</i> studies revealed that the DDS effectively reduced leptin receptor expression and alleviated the inflammatory environment, thereby promoting regeneration in degenerated IVDs. We propose that the DDS represents a promising novel approach for treating IDD and may also be beneficial for other degenerative diseases linked to leptin pathway dysfunction.