2. Academic Validation
  3. Targeted delivery of BMPR2 mRNA attenuates pulmonary arterial hypertension by reversing pulmonary vascular remodeling

Targeted delivery of BMPR2 mRNA attenuates pulmonary arterial hypertension by reversing pulmonary vascular remodeling

  • Acta Pharm Sin B. 2025 Oct;15(10):5416-5430. doi: 10.1016/j.apsb.2025.07.004.
Yan Cao 1 2,  Runyuan Wang 1,  Xiaoyan He 1,  Yan Ding 1,  Yan Chang 1,  Runyue Yang 3,  Guisheng Zhong 4,  Huiying Yang 5,  Jianfeng Li 1 6 7
Affiliations

Affiliations

  • 1 School of Life Science and Technology & State Key Laboratory of Advanced Medical Materials and Devices, ShanghaiTech University, Shanghai 201210, China.
  • 2 Department of Pharmacy, School of Health and Nursing, Wuxi Taihu University, Wuxi 214063, China.
  • 3 Department of Endocrinology and Metabolism, Zhongshan Hospital, Fudan University, Shanghai 200030, China.
  • 4 iHuman Institute, ShanghaiTech University, Shanghai 201210, China.
  • 5 Department of Pharmacy, Huashan Hospital, Fudan University, Shanghai 200040, China.
  • 6 Shanghai Clinical Research and Trial Center, Shanghai 201210, China.
  • 7 Gene Editing Center, School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China.
PMID: 41132833 DOI: 10.1016/j.apsb.2025.07.004
Abstract

Disrupted bone morphogenetic protein type 2 receptor (BMPR2) signaling in endothelial cells drives pulmonary arterial hypertension (PAH). However, targeted recovery of this signaling pathway by lipid nanoparticles (LNPs) has not been explored as a therapy. Here, we employed Design of Experiments to optimize the delivery efficiency of LNPs targeting pulmonary endothelial cells developed by our laboratory, resulting in a remarkable 35-fold increase in a simplified three-component formulation without helper lipids. Administration of BMPR2 mRNA LNPs effectively reversed established PAH in two experimental rat models (monocrotaline or SU5416-hypoxia) by reversing pulmonary vascular remodeling. Specifically, BMPR2 mRNA LNPs replenished the expression of BMPR2 protein and subsequently activated downstream pathways, as confirmed by elevated levels of p-SMAD1/5/9 and ID1 proteins. The relief of pulmonary arterial occlusion was demonstrated by thinned pulmonary arterial media and decreased proportion of full muscularized vessels. Alleviation of right ventricular hypertrophy was indicated by declined Fulton index, the cross-sectional area of right ventricular cardiomyocytes as well as Collagen deposition. Effective recovery of right ventricular function was evidenced by increased pulmonary artery flow acceleration time/pulmonary artery flow ejection time ratio. These findings underscore the potential of restoring BMPR2 signaling through pulmonary endothelial cell-specific LNPs for treating PAH.

Keywords

BMPR2 restoration; Design of Experiments; Helper lipid-free LNPs; Lipid nanoparticles; Protein replacement therapy; Pulmonary arterial hypertension; Pulmonary endothelial targeting; mRNA delivery.

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