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<p>The persistent opening of the mitochondrial permeability transition pore (mPTP) plays a critical role in bronchial asthma pathogenesis. The ATP synthase c subunit (c subunit) constitutes a core component of mPTP. A novel c subunit inhibitor, 1,3,8-triazaspiro [4.5] decane derivatives (PP10), effectively suppresses pathological mPTP opening without impairing ATP synthesis. Although intraperitoneal PP10 administration mitigates airway inflammation in asthmatic mice, its hydrophobicity hinders inhaled delivery to airway epithelial mitochondria, requiring penetration of the mucus layer, cell membrane, and mitochondrial outer membrane. To overcome this, we developed inhalable human serum albumin-triphenylphosphine-polyethylene glycol-PP10 nanoparticles (HSA-TPP-PEG-PP10 NPs). These NPs demonstrated efficient mucus penetration, high drug loading, mitochondria-targeting capability, and biosafety. They suppressed house dust mite/lipopolysaccharide (HDM/LPS)-induced mPTP opening, inhibited the mitochondrial DNA (mtDNA)-cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway, reduced inflammation in human bronchial epithelial (HBE) cells, and alleviated airway inflammation in asthmatic mice upon inhalation.</p> Graphical Abstract <p></p>

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Targeted inhibition of ATP synthase subunit c by pp10-loaded inhalable albumin nanoparticles ameliorates airway inflammation in asthma

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月9日

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  • Decai Wang,
  • Tong Zhou,
  • Yalan Cui,
  • Chen Bao,
  • Shuaiqi Yuan,
  • Chengchen Wu,
  • Qian Liu,
  • Chao Liu,
  • Jiannan Hu,
  • Mingrong Liu,
  • Ziling Li,
  • Xinyue Ma,
  • Yunfei Zhu,
  • Jingjing Sun,
  • Shuyun Xu,
  • Yuzhou Wu

摘要

The persistent opening of the mitochondrial permeability transition pore (mPTP) plays a critical role in bronchial asthma pathogenesis. The ATP synthase c subunit (c subunit) constitutes a core component of mPTP. A novel c subunit inhibitor, 1,3,8-triazaspiro [4.5] decane derivatives (PP10), effectively suppresses pathological mPTP opening without impairing ATP synthesis. Although intraperitoneal PP10 administration mitigates airway inflammation in asthmatic mice, its hydrophobicity hinders inhaled delivery to airway epithelial mitochondria, requiring penetration of the mucus layer, cell membrane, and mitochondrial outer membrane. To overcome this, we developed inhalable human serum albumin-triphenylphosphine-polyethylene glycol-PP10 nanoparticles (HSA-TPP-PEG-PP10 NPs). These NPs demonstrated efficient mucus penetration, high drug loading, mitochondria-targeting capability, and biosafety. They suppressed house dust mite/lipopolysaccharide (HDM/LPS)-induced mPTP opening, inhibited the mitochondrial DNA (mtDNA)-cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway, reduced inflammation in human bronchial epithelial (HBE) cells, and alleviated airway inflammation in asthmatic mice upon inhalation.

Graphical Abstract