Intranasal delivery of R8-modified circNFXL1 liposomes ameliorates Su5416-induced pulmonary arterial hypertension in C57BL/6 mice.

Abstract

Background: Pulmonary arterial hypertension (PAH) is a progressive, life-threatening condition characterized by increased pulmonary vascular resistance and right ventricular hypertrophy (RVH). Current treatments primarily alleviate symptoms but do not effectively target the underlying molecular mechanisms driving the disease. This study aimed to evaluate the therapeutic potential of R8-modified liposomal delivery of circNFXL1, a circular RNA, in a mouse model of PAH.

Methods: R8-circNFXL1 liposomes were synthesized and characterized for their physicochemical properties, including encapsulation efficiency. PAH was induced in C57BL/6 mice using a combination of subcutaneous Su5416 administration and hypoxic exposure. Intranasal delivery of R8-circNFXL1 was performed, and therapeutic effects were assessed using echocardiography and hemodynamic measurements. Molecular mechanisms were explored through analysis of the miR-29b/Kcnb1 axis, a regulatory pathway in PAH.

Results: The R8-circNFXL1 liposomes demonstrated optimal physicochemical properties, including high encapsulation efficiency. Treatment with R8-circNFXL1 significantly reduced RVH, improved cardiac function, and mitigated pulmonary vascular remodeling compared to untreated PAH controls. Molecular analysis revealed that R8-circNFXL1 modulated the miR-29b/Kcnb1 axis, providing insights into its mechanism of action.

Conclusions: R8-circNFXL1 liposomes offer a promising, targeted therapeutic strategy for PAH by addressing underlying molecular mechanisms. This approach has potential implications for developing alternative treatments to improve disease management and outcomes in PAH.