Circular RNA-Directed Therapeutic Strategy for Cold-Induced Diabetic Macrovascular Disease.

Aims: This study aims to elucidate the molecular mechanisms underlying the alleviation of cold-climate-induced diabetic macrovascular disease (DM-MVD) by targeting hsa_circ_0010154 with gold nanoparticles (AuNPs)-mediated antisense oligonucleotides (ASOs) delivery, combined with aerobic exercise, and to explore the therapeutic effects on glucose and lipid metabolism, inflammation, and oxidative stress. Results: Significant upregulation of hsa_circ_0010154 in DM-MVD was confirmed through bioinformatics analysis and qRT-PCR validation. The constructed gold nanoparticles-mediated antisense oligonucleotides delivery (AuNPs@ASO) complex exhibited efficient reactive oxygen species-responsive release and effective cellular uptake. Silencing hsa_circ_0010154 led to improved endothelial cell function, reduced inflammation markers, enhanced lipid metabolism, and reduced oxidative stress responses. In vivo studies demonstrated improved cardiac function, vascular remodeling, and enhanced antioxidant enzyme activity. Innovation: This study introduces a novel approach utilizing AuNPs@ASO targeting hsa_circ_0010154 in conjunction with aerobic exercise to address the complex pathophysiology of cold-climate-induced DM-MVD, presenting a targeted, low-toxicity therapeutic strategy with promising translational potential. Conclusion: The combined treatment of AuNPs@ASO and aerobic exercise, targeting hsa_circ_0010154, effectively modulates critical pathological pathways involved in DM-MVD, offering a precise and innovative approach for tackling this condition, with implications for clinical translation. Antioxid. Redox Signal. 00, 000-000.