Gingerol-loaded hollow manganese dioxide nanoparticles attenuate intervertebral disc oxidative stress

Intervertebral disc degeneration (IVDD) is a major cause of chronic low back pain, thus therapies capable of halting its progression are urgently needed. Evidence suggests that oxidative stress is a key accelerator of IVDD, making interventions targeting reactive oxygen species (ROS) highly promising. The natural compound 6-gingerol has been proved to possess potent antioxidant properties, however, its therapeutic application is hampered by poor solubility, rapid clearance, and lack of targeted delivery. To address these limitations and investigate the effect of 6-gingerol on IVDD, we developed an integrated nanoplatform (H@G) by encapsulating 6-gingerol within hollow manganese dioxide nanoparticles. The synthesized H@G nanoparticles exhibited a uniform hollow spherical structure (∼100 nm), a high surface area, and successful drug loading without altering the carrier morphology. The nanoparticles demonstrated good stability in physiological media but underwent rapid degradation under acidic conditions and in an H₂O₂ microenvironment. Accordingly, H@G exhibited pH- and H₂O₂-responsive drug release. The H@G nanoparticles also displayed superoxide dismutase-like, hydroxyl radical-scavenging, and catalase-like activities in a concentration-dependent manner. Under H₂O₂-induced oxidative stress, H@G significantly enhanced the viability of nucleus pulposus cells, potently scavenged both intracellular and mitochondrial ROS, restored mitochondrial membrane potential, and preserved cristae ultrastructure. Furthermore, H@G restored extracellular matrix homeostasis under oxidative stress by upregulating anabolic markers (ACAN and COL2A1) and downregulating catabolic enzymes (MMP3 and MMP13). Collectively, our results demonstrate that the H@G nanosystem effectively attenuates oxidative stress, maintains mitochondrial homeostasis, and promotes matrix anabolism in NPCs, which provides a promising and targeted strategy to attenuate oxidative stress and disc degeneration in IVDD.