MnO₂-armored human embryonic stem cell exosomes delay intervertebral disc degeneration via synergistic antioxidant defense and regenerative signal delivery

The oxidative and inflammatory microenvironment impairs the regeneration and homeostasis of nucleus pulposus cells. This microenvironment is characterized by high levels of reactive oxygen species (ROS), mitochondrial dysfunction, and NLRP3 inflammasome-induced pyroptosis. These changes accelerate cellular senescence and disrupt the metabolic homeostasis of the extracellular matrix (ECM). Exosomes derived from human embryonic stem cells (hESCs) hold great potential for regeneration and inflammation control but lack inherent antioxidant protection. In the highly oxidative microenvironment of degenerated intervertebral discs, these exosomes degrade rapidly, which significantly limits their therapeutic efficacy. To address this issue, we developed a manganese dioxide nanoplate-armored exosome system (hESC-Exos@MnO₂). The system exerts its therapeutic effects through a synergistic, multilevel mechanism. First, the MnO₂ nanoarmor shields the exosomes; second, MnO₂ is degraded in the acidic, H₂O₂-rich degenerative microenvironment to scavenge reactive oxygen species (ROS); finally, the released Mn²⁺ may exert a synergistic effect with exosomes on ECM remodeling and microenvironment repair. In the restored microenvironment, exosomes efficiently deliver regenerative signaling molecules to regulate key signaling pathways such as p53 and can partially alleviate oxidative stress-induced cell-cycle arrest, inhibit cell death and senescence, and promote ECM synthetic metabolism. Our study revealed that hESC-Exos@MnO₂ attenuates oxidative injury, partially preserved mitochondrial membrane potential, and ameliorates ECM homeostasis. In a rat model of intervertebral disc degeneration, this treatment effectively maintenance intervertebral disc height. This work introduces a new "catalytic scavenging-bioremediation" strategy, providing a modular nanoplatform with high applicability for intervertebral disc regeneration and potential utility in treating other degenerative diseases.