Synergistic therapy with cerium-based nanozymes and mitochondrial RNA polymerase inhibition combats mitochondrial double-stranded RNA-mediated inflammation in osteoarthritis.

Recent research has demonstrated that the accumulation of excessive mitochondrial double-stranded RNA (mt-dsRNA) plays a significant role in inflammatory processes. Although interventions targeting mt-dsRNA release have shown efficacy in treating various inflammatory diseases, their therapeutic potential in osteoarthritis (OA) remains unclear. This study elucidates the pivotal role of mt-dsRNA in the pathogenesis of OA. Advancing beyond traditional mt-dsRNA suppression methods, we have developed cerium-integrated dendritic mesoporous silica nanoparticles (Ce@DMSN) designed to deliver the mt-dsRNA release inhibitor IMT1, referred to as Ce@DMSN-IMT1 nanoparticles. These biocompatible nanoparticles possess dual functionalities: a robust mt-dsRNA degradation capability and effective inhibition of dsRNA release, leading to substantial anti-inflammatory effects. Intra-articular administration of Ce@DMSN-IMT1 nanoparticles significantly reduced cartilage degradation and synovitis in rat models with destabilized medial meniscus by specifically targeting the mt-dsRNA pathway. This study presents the first instance of nanozyme-mediated mt-dsRNA hydrolysis for the control of inflammation, with the multifunctional Ce@DMSN-IMT1 system offering a synergistic therapeutic approach that holds promise as a disease-modifying strategy for OA. STATEMENT OF SIGNIFICANCE: Therapeutic targeting of mitochondrial double-stranded RNA (mt-dsRNA) to mitigate osteoarthritis (OA) progression has not been previously reported. The utilization of cerium for RNA degradation as an anti-inflammatory strategy remains undocumented. The application of mt-dsRNA release inhibitor to attenuate OA progression has not been previously documented. The dual mechanism combining mt-dsRNA degradation and release inhibition enhances anti-inflammatory effects, conferring superior therapeutic outcomes compared to traditional single-target approaches. This nanoplatform attenuates mitochondrial dysfunction and suppresses retinoic acid-inducible gene I (RIG-I) and melanoma differentiation-associated gene 5 (MDA5) signaling pathway activation. The Drug-Cerium nanozyme represents a synergistic and disease-modifying therapeutic strategy for osteoarthritis.