Targeting MT-tsRNA IDDMT with Nanoparticles to Annulus Fibrosus: A Novel Therapeutic Approach for Intervertebral Disc Degeneration.

Abstract

Annulus fibrosus (AF) injury is a significant cause of NP protrusion and intervertebral disc degeneration (IDD). Currently, the molecular mechanisms of IDD remain unclear, and there is a lack of methods for early diagnosis and targeted drug delivery through the circulatory system. This study focuses on the mitochondria-derived tsRNA, IDDMT (IDD-related mitochondrial-derived tsRNA, mt-TRF3-24-AspGTC), which is significantly upregulated in degenerated AF tissues of intervertebral discs. Mechanistically, IDDMT overexpression interacts with IMPDH2, activating the NF-κB signaling pathway and leading to mitochondrial dysfunction, ROS production, and apoptosis in AF cells. To address this issue, a nanocarrier system, UCNP (NaGdF₄@NaErF₄@NaLuF₄ @MSN@ZIF-8@IN-IDDMT@Suc-(GfO)₉), capable of dual-modal imaging with MRI and NIR II, for targeted delivery of IDDMT inhibitors to repair AF damage and slow the progression of IDD is developed. In vitro and in vivo experiments have confirmed the effectiveness of UMZG in restoring mitochondrial dynamics, reducing ROS production, inflammation, and cell apoptosis. This innovative therapeutic approach, which integrates dual-modal imaging capabilities, offers a new avenue for the early treatment of IDD.