A multifunctional mitochondria-protective gene delivery platform promote intervertebral disc regeneration.

Abstract

Intervertebral disc degeneration (IDD) is a deleterious condition driven by localized inflammation and the associated disruption of the normal homeostatic balance between anabolism and catabolism, contributing to progressive functional abnormalities within the nucleus pulposus (NP). Despite our prior evidence demonstrating that a miR-21 inhibitor can have regenerative effects that counteract the progression of IDD, its application for IDD treatment remains limited by the inadequacy of current local delivery systems. Here, an injectable tannic acid (TA)-loaded hydrogel gene delivery system was developed and used for the encapsulation of a multifunctional mitochondria-protecting gene nanocarrier (PHs). This engineered platform was designed for the sustained on-demand delivery of both miR-21 inhibitor and ss-31 (mitochondrial-targeted peptide) constructs to the NP. This prepared hydrogel could be implanted into the intervertebral disc using a minimally invasive approach whereupon it was able to rapidly release TA. Sustained PHs release was then achieved as appropriate through a mechanism mediated by the activity of MMP-2. Following the targeted uptake of PHs by degenerated NP cells, the subsequent release of encapsulated miR-21 inhibitor suppressed apoptotic cell death and modulated the metabolism of the extracellular matrix (ECM) by targeting the Spry1 gene. At the same time, ss-31 was able to target damaged mitochondria and alleviate inflammatory activity via the suppression of mitochondrial ROS-NLRP3-IL-1β/Caspase1 pathway activity. Synergistic ECM regeneration and anti-inflammatory effects were sufficient to provide therapeutic benefits in an in vivo model of IDD. Together, these results thus highlight this hydrogel-based gene delivery platform as a promising novel approach to the treatment of IDD.