Modulating tumor collagen fiber alignment for enhanced lung cancer immunotherapy via inhaled RNA

Bin Hu, William Stewart, Qijing Chen, Chenshuang Zhang, Zhixiang Liu, Xiaoyang Xu () and Xue-Qing Zhang ()
Additional contact information
Bin Hu: Shanghai Jiao Tong University
William Stewart: New Jersey Institute of Technology
Qijing Chen: Shanghai Jiao Tong University
Chenshuang Zhang: Shanghai Jiao Tong University
Zhixiang Liu: New Jersey Institute of Technology
Xiaoyang Xu: New Jersey Institute of Technology
Xue-Qing Zhang: Shanghai Jiao Tong University

Nature Communications, 2025, vol. 16, issue 1, 1-18

Abstract: Abstract The clinical effectiveness of immunotherapies for lung cancers has been greatly hindered by the immune-excluded and immunosuppressive tumor microenvironment (TME) and limited pulmonary accessibility of therapeutics. Here, we develop an inhalable lipid nanoparticle (LNP) system that enables simultaneous delivery of mRNA encoding anti-discoidin domain receptor 1 (DDR1) single-chain variable fragments (mscFv) and siRNA targeting PD-L1 (siPD-L1) into pulmonary cancer cells. The secreted anti-DDR1 scFv blocks the binding of DDR1 extracellular domain to collagen, disrupting collagen fiber alignment and reducing tumor stiffness, thereby facilitating T cell infiltration. Meanwhile, PD-L1 silencing alleviates immunosuppression and preserves T cell cytotoxicity. In vivo results demonstrate that mscFv@LNP induces collagen fiber rearrangement and diminishes tumor stiffness. In both orthotopic and metastatic mouse models of lung cancer, inhalation of mscFv/siPD-L1@LNP promotes tumor regression and extends overall survival. This strategy could be broadly applicable to solid tumors and benefit other cancer immunotherapies by addressing the universally hostile TME involved in tumor progression.

Date: 2025
References: Add references at CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-025-63415-0 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-63415-0

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-025-63415-0

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().