Treatment Of Dop With A Dna Tetrahedron-Based Ferroptosis Inhibitor

The aim of this study was to synthesize a functionalized ASRPFi DNA tetrahedral-based inhibitor, targeting ferroptosis and promoting bone regeneration for the treatment of diabetic osteoporosis (DOP) and fracture. We establish type 2 diabetic (T2DM) model and employ lncRNA-seq, Ribo-seq, and gene transfection silencing techniques to explore molecular targets and specific mechanisms that regulate ferroptosis. It showed that the level of ferroptosis increased while osteogenic differentiation potential of BMSCs was inhibited in the diabetic microenvironment, leading to a reduction in bone mass, destruction of bone microstructure, and impaired bone formation. Mechanistically speaking, LOC66961 encoded a 53-amino acid peptide, named as a small regulatory peptide of ferroptosis (ASRPF), which was highly expressed in the diabetic bone microenvironment, binding to Slc40a1(FPN) to inhibit its transcription, leading to reduced iron export and intracellular iron accumulation, promoting ferroptosis, and thus inhibiting osteogenesis of BMSCs. Finally, a functionalized ASRPFi DNA tetrahedral-based inhibitor targeting ferroptosis for the treatment of DOP and fractures was developed, clarifying the molecular mechanisms and application prospects from in vitro and in vivo perspectives. These findings suggest that ASRPFi functionalized DNA tetrahedron-based ferroptosis suppressing nanoparticles have a promising potential for the treatment of DOP and other ferroptosis-related diseases.