Herba Lysimachiae Polysaccharide‐Modified Selenium Nanoparticles Alleviate Oxidative Injury in Kidney Stones via TOMM22‐Regulated Mitophagy Activation

ABSTRACT Pharmacological treatments for kidney stones remain limited, with oxidative stress and injury to renal tubular epithelial cells (RTECs) as key pathological drivers. We prepared a novel Herba Lysimachiae polysaccharide‐modified selenium nanoparticle (HLP‐SeNPs) formulation that enhances the stability and antioxidant activity of selenium nanoparticles (SeNPs) to alleviate oxalate‐induced renal injury. In vivo and in vitro studies showed that HLP‐SeNPs possess pronounced anti‐oxidative stress capacity, restore mitochondrial membrane potential, alleviate mitochondrial damage, reduce RTEC death, and inhibit renal calcium oxalate (CaOx) crystal deposition. Mechanistically, HLP‐SeNPs downregulate TOMM22 (translocase of the outer mitochondrial membrane 22, a core TOM complex subunit) to activate PINK1‐Parkin‐mediated mitophagy, thereby effectively limiting oxidative stress‐induced injury at its source. These findings indicate that HLP‐SeNPs exert substantial renoprotective effects and prevent CaOx stone formation, providing an experimental foundation for mitochondria‐targeted nanotherapeutics in kidney stone disease and highlighting the potential of integrating traditional Chinese medicine with nanomaterials.