Integrin/CD44-targeted liposomes remodel the pulmonary microenvironment to alleviate acute exacerbation of pulmonary fibrosis

  • J Control Release. 2026 Jan 10:389:114427. doi: 10.1016/j.jconrel.2025.114427.
Xinmei Huang  1 ,  Yingwei Zhang  1 ,  Xin Yan  1 ,  Qiuyan Huang  2 ,  Min Chen  2 ,  Cheng Jiang  1 ,  Zimu Wang  1 ,  Di Sun  1 ,  Yan Li  1 ,  Jingjing Ding  1 ,  Xiaohua Qiu  3 ,  Mengshu Cao  4 ,  Yonglong Xiao  5
Affiliations
  • 1. Department of Respiratory and Critical Care Medicine, Nanjing Drum Tower Hospital, Clinical College of Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing 210000, China; Department of Respiratory and Critical Care Medicine, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing 210000, China; Department of Respiratory and Critical Care Medicine, Nanjing Drum Tower Hospital Clinical College of Nanjing Medical University, Nanjing 210000, China; Nanjing Institute of Respiratory Diseases, Nanjing 210000, China.
  • 2. Department of Respiratory and Critical Care Medicine, Nanjing Drum Tower Hospital, Clinical College of Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing 210000, China.
  • 3. Department of Respiratory and Critical Care Medicine, Nanjing Drum Tower Hospital, Clinical College of Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing 210000, China; Department of Respiratory and Critical Care Medicine, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing 210000, China; Department of Respiratory and Critical Care Medicine, Nanjing Drum Tower Hospital Clinical College of Nanjing Medical University, Nanjing 210000, China; Nanjing Institute of Respiratory Diseases, Nanjing 210000, China.. Electronic address: [email protected].
  • 4. Department of Respiratory and Critical Care Medicine, Nanjing Drum Tower Hospital, Clinical College of Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing 210000, China; Department of Respiratory and Critical Care Medicine, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing 210000, China; Department of Respiratory and Critical Care Medicine, Nanjing Drum Tower Hospital Clinical College of Nanjing Medical University, Nanjing 210000, China; Nanjing Institute of Respiratory Diseases, Nanjing 210000, China.. Electronic address: [email protected].
  • 5. Department of Respiratory and Critical Care Medicine, Nanjing Drum Tower Hospital, Clinical College of Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing 210000, China; Department of Respiratory and Critical Care Medicine, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing 210000, China; Department of Respiratory and Critical Care Medicine, Nanjing Drum Tower Hospital Clinical College of Nanjing Medical University, Nanjing 210000, China; Nanjing Institute of Respiratory Diseases, Nanjing 210000, China.. Electronic address: [email protected].
PMID: 41265642 DOI: 10.1016/j.jconrel.2025.114427
Abstract

Acute exacerbation of idiopathic pulmonary fibrosis (AE-IPF) poses a significant clinical challenge due to its high morbidity and mortality, coupled with a lack of effective targeted therapies. Here, utilizing single-cell transcriptomic analysis and validation in AE-IPF patient samples, we identified Integrin and CD44 as markedly upregulated in injured alveolar type II cells and myofibroblasts, highlighting their potential as pathological delivery targets in AE-IPF. Based on these findings, we developed a dual-targeted liposomal nanoplatform (ND-RHL) co-encapsulating nintedanib and dexamethasone, specifically engineered to exploit Integrin/CD44 overexpression for pulmonary precise drug delivery and synergistic anti-fibrotic and anti-inflammatory effects. ND-RHL exhibited favorable physicochemical characteristics, efficient dual-drug loading, and selective accumulation in Integrin/CD44-high cells both in vitro and in vivo. In a murine model of AE-IPF, intratracheal administration of ND-RHL markedly improved survival, mitigated lung inflammation and fibrosis, and preserved pulmonary architecture, with minimal systemic toxicity. Mechanistically, transcriptomic profiling and immune phenotyping demonstrated that ND-RHL reversed AE-induced gene expression patterns and inhibited pivotal signaling pathways, including PI3K-AKT-mTOR, Wnt/β-catenin, and NF-κB-PPARγ, thereby orchestrating the remodeling of both immune and extracellular matrix microenvironments. This study presents ND-RHL as a mechanistically informed, cell-targeted nanotherapeutic with robust therapeutic potential and translational promise for the treatment of AE-IPF and related fibrotic lung diseases.

Keywords
Acute exacerbation of idiopathic pulmonary fibrosis (AE-IPF); Dexamethasone; Integrin/CD44 targeting; Liposomal drug delivery; Nintedanib.
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