Magnetofection-mediated siRNA delivery ameliorates cartilage damage in Kashin-Beck disease via targeting SIRT3 and protecting primary cilia.

RATIONALE: Kashin-Beck disease (KBD) is an endemic osteochondropathy caused by T-2 toxin, however, the molecular mechanism underlying T-2 toxin-induced chondrocyte damage remains unclear. This study aimed to elucidate the pathogenic role of T-2 toxin in KBD and develop an EMF-augmented nanotherapy for KBD-related cartilage damage. METHODS: This study investigated T-2 toxin-induced chondrocyte damage by evaluating protein acetylation, primary cilia integrity and the levels of chondrogenic markers (Sox9, Col2a1). In vitro experiments were performed via pharmacological and genetic SIRT3 inhibition. To protect chondrocytes, si-SIRT3@SPIONs were fabricated, and EMF was applied to improve cell transfection and silencing efficiency. A KBD model in SD rats was used to validate the in vivo therapeutic effect; immunohistochemical staining and micro-CT scanning and reconstruction were performed to comprehensively evaluate in vivo treatment efficacy. RESULTS: Pathological SIRT3 overexpression induced by T-2 toxin disrupted chondrocyte protein acetylation, impaired primary cilia integrity, and suppressed the gene expression of chondrogenic markers. SIRT3 inhibition efficiently protected T-2 toxin-induced chondrocyte cytotoxicity in vitro. Furthermore, EMF-augmented si-SIRT3@SPIONs treatment ameliorated cartilage damage, preserved matrix composition and restored normal chondrocyte phenotype in KBD model rats. CONCLUSIONS: T-2 toxin induces chondrocyte injury and promotes KBD progression mainly by disrupting primary cilia integrity and protein acetylation, with SIRT3 overexpression acting as a mediating factor. The EMF-augmented si-SIRT3@SPIONs therapy can effectively protect T-2 toxin-induced primary cilia damage and cartilage degeneration, thus providing a promising therapeutic modality for KBD.