PIAS3 CircRNA‐Loaded Lipid Nanoparticles Restore ALOX15 SUMOylation to Suppress Cementoblast Ferroptosis and Attenuate Orthodontically Induced Root Resorption

Excessive orthodontic compression induces cementoblast dysfunction and contributes to orthodontically induced root resorption (OIRR), yet the molecular mechanisms linking mechanical stress to cementoblast ferroptosis remain unclear. Compression-induced PIAS3 loss attenuates SUMO3-dependent ALOX15 SUMOylation and impairs ALOX15 ubiquitination and proteasomal degradation, thereby promoting lipid peroxidation and cementoblast ferroptosis. Based on these findings, PIAS3 circRNA-loaded uridine-derived lipid nanoparticles (PIAS3-OLNPs) were developed, which efficiently restored PIAS3 expression and inhibited cementoblast ferroptosis and subsequent osteoclast differentiation. Moreover, the incorporation of PIAS3-OLNPs into an injectable F127DA hydrogel prolonged local retention and sustained PIAS3 expression in the gingival sulcus, thereby inhibiting cementoblast ferroptosis and osteoclastogenesis and preserving root integrity in vivo. Collectively, this study establishes PIAS3-mediated ALOX15 SUMOylation as a key mechanism that restrains cementoblast ferroptosis and demonstrates that restoring this pathway through local PIAS3 circRNA delivery offers a therapeutic strategy for OIRR and potentially other ferroptosis-related disorders.