A MAM-targeted integrated atomic-precision MnSe janus nanozyme platform inhibits pyroptosis and ferroptosis for intervertebral disc degeneration therapy

Abstract

Aberrant endoplasmic reticulum (ER)–mitochondria crosstalk at mitochondria-associated ER membranes (MAMs) drives oxidative stress, calcium dysregulation, pyroptosis, and ferroptosis in nucleus pulposus cells, accelerating intervertebral disc degeneration (IVDD). Nanozymes that mimic antioxidant enzymes and remodel the oxidative stress microenvironment are promising for IVDD treatment, but their efficacy is limited by low enzyme-like activity and poor targeting of MAMs. To address this, we developed a space-confined pyrolysis strategy to synthesize N/O co-doped hollow bamboo-like porous carbon nanotubes loaded with atomically Janus MnSe dual atoms, and functionalization with the MAM-targeting protein GRP75 and σ1R-regulator CGI1746 yielded GC-MnSe DA /BCNT, an integrated nanozyme platform for precise IVDD intervention. The hollow BCNT framework exposed atomically dispersed MnSe sites, while the MnSeN 5 O Janus active center optimizes Mn’s local electronic structure via Se-mediated p-d orbital hybridization, promoting electron transfer and lowering the reaction energy barrier, thereby boosting SOD-, CAT-, and GPx-like activities. This platform exhibited high biosafety and potent multi-enzyme antioxidant activity, enabling efficient ROS scavenging and inhibition of lipid peroxidation. Importantly, it restored the integrity of MAMs and mitochondrial function, maintained Ca 2 ⁺ homeostasis, and suppressed NLRP3-mediated pyroptosis and ferroptosis, thereby delaying IVDD progression. This work provides an efficient, safe, and precise new strategy for the treatment of degenerative and inflammatory diseases.