Nanozyme bionics mitochondrial revitalizer suppresses ferroptosis in nucleus pulposus cells for disc regeneration

Intervertebral disc degeneration (IDD) is a leading cause of low back pain, which is characterized by a degenerative microenvironment with reactive oxygen species (ROS) accumulation and ferrous ion overload, resulting in oxidative stress and ferroptosis in nucleus pulposus cells (NPCs). To address these clinical challenges, polyhydroxy fullerol with excellent water solubility is developed to serve as the mitochondrial revitalizer of nanozyme bionics. Given its unique carbon cage structure, this novel fullerol can scavenge ROS and chelate excess ferrous ions within the microenvironment, thereby effectively maintaining mitochondrial homeostasis and suppressing NPC ferroptosis in the IDD progression. Through RNA sequencing and bioinformatic analyses, we identify the Rap1 signaling as a crucial role in fullerol-mediated mitochondrial protection and ferroptosis resistance. Specifically, fullerol promotes the formation of Rap1-GTP that further interacts with Keap1 to dissociate Nrf2, thereby activating the Nrf2 pathway to exert anti-oxidative and anti-ferroptotic effects on NPCs. Additionally, the therapeutic potential of fullerol as well as the underlying mechanism have been verified in a puncture-induced IDD model, proving the effectiveness of this nanomaterial-based strategy for disc regeneration. In summary, this study elucidates the biomechanisms behind the cytoprotection of fullerol by suppressing ferroptosis, making it a highly promising nanomaterial for clinical IDD treatment.