Modulation of Inflammation and Regeneration in the Intervertebral Disc Using Enhanced Cell-Penetrating Peptides for MicroRNA Delivery

Abstract

Back pain is a global epidemiological and socioeconomic problem affecting up to 80% of people at some stage during their life and is often due to degeneration of the intervertebral disc (IVD). Therapies aimed at restoring the intradiscal space have predominantly focused on delivery of biomaterials, cells, or growth factors, among others, with variable degrees of success. While viral gene delivery strategies have emerged as promising therapeutic options in recent years, these approaches often have off-target effects and are associated with immunogenicity risks and other comorbidities. Consequently, nonviral methods have gained traction as potential avenues for gene delivery. Herein, enhanced cell-penetrating peptide (CPP) systems are used to deliver microRNAs in an in vitro and ex vivo model of disc degeneration. The data suggest that nanoparticle complexation of CPPs with (miR-221-inhibitor + miR-149-mimic) promotes protective effects in nucleus pulposus cells challenged with inflammatory cytokines TNF-α and IL-1β. Specifically, increases in matrix deposition, significant decreases in the secretion of an array of inflammatory cytokines, and decreased expression of matrix degradation enzymes MMP13 and ADAMTS5 are observed. These miR-CPP nanocomplexes can be further employed for targeting of the pericellular matrix space through homing, thus providing a promising approach for therapies of the intradiscal space.