Mitochondria-Targeting Polymeric Micelles for Intervertebral Disc Degeneration Alleviation via Coordinated Cascade Energetic Intervention

Mitochondrial dysfunction plays a pivotal role in intervertebral disc degeneration (IVDD) by disrupting mitochondrial bioenergetic balance, which leads to impaired ATP synthesis, accumulation of ROS, degradation of the extracellular matrix, and degeneration of nucleus pulposus cells. Despite advances in single or multiple therapeutic strategies, a more comprehensive and coupled cascade regulation strategy that fundamentally restores mitochondrial function is urgently needed, but rarely reported. Mitochondrial bioenergetics is cascade-regulated by the interplay between the OXPHOS and the TCA cycle, where impairment of either disrupts energy homeostasis, necessitating coordinated cascade therapeutic intervention. Hence, mitochondria-targeting polymeric micelles (AKG@PIDE-OPDEA) were constructed via self-assembly of an amphiphilic polymer (PIDE-OPDEA) and α-ketoglutarate (AKG). AKG@PIDE-OPDEA enabled a synergistic mitochondrial repair approach by addressing both the "raw materials" (AKG supply) and the "production line" (mitochondrial respiratory function). Through this concatenation-like therapy, AKG@PIDE-OPDEA restores the mitochondrial bioenergetics in degenerated NPCs and alleviates ECM degradation. In terms of mechanism, it restrains mitochondrial hyperfragmentation and mitigates mitochondrial matrix swelling, which effectively limit stress-induced mtDNA leakage, subsequently inhibiting cGAS-STING pathway activation and reducing downstream inflammation. Overall, this study demonstrates the feasibility of an intramitochondrial energy chain therapy, offering a novel strategy for the treatment of IVDD.