2. Academic Validation
  3. Integrin/CD44-targeted liposomes remodel the pulmonary microenvironment to alleviate acute exacerbation of pulmonary fibrosis

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

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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