Biomimetic nanoplatforms modulating mitochondrial pathways in IVDD.

OBJECTIVE

To develop and evaluate a mitochondria-targeted biomimetic nanoplatform (nMitoQ-SNA-CMT) for the treatment of intervertebral disc degeneration (IVDD).

METHODS

A rat IVDD model and an H2O2-induced oxidative stress model in nucleus pulposus cells (NPCs) were established to investigate the effects of nMitoQ-SNA-CMT on mitochondrial function, oxidative stress, mitophagy, inflammatory signaling, and cellular senescence. Molecular, cellular, and histological analyses were used to evaluate therapeutic efficacy in vitro and in vivo.

RESULTS

nMitoQ-SNA-CMT efficiently targeted mitochondria, scavenged excessive reactive oxygen species (ROS), and silenced miR-141-3p, thereby activating SESN2-dependent UPRmt and mitophagy. This dual action markedly reduced mitochondrial DNA release and suppressed cGAS-STING pathway activation, leading to attenuation of NPC senescence, inflammatory responses, and extracellular matrix degradation. In IVDD rat models, nMitoQ-SNA-CMT significantly restored disc structure and function and outperformed free MitoQ and non-coated nanoparticles.

CONCLUSION

nMitoQ-SNA-CMT represents a potent and safe therapeutic strategy for IVDD by coordinately regulating mitochondrial oxidative stress, mitophagy, and innate immune activation, providing a promising platform for precision nanomedicine in degenerative disc diseases.