Inhaled nucleic acid therapeutics for respiratory diseases: delivery barriers, translational challenges, and emerging solutions.
- 1Center for Nanomedicine and Gene Therapy, School of Pharmacy and Bioengineering, Chongqing University of Technology, Chongqing 400054, China.
- 2School of Public Health, Chongqing Medical University, Chongqing 401331, China.
- 3The WhiteOak Group, Inc., Rockville, MD 20855, USA.
Abstract
Pulmonary delivery of nucleic acid therapeutics represents a transformative strategy for treating a broad spectrum of respiratory diseases, including lung cancer, pulmonary fibrosis, chronic obstructive pulmonary disease, and acute lung injury. Despite their promise, effective clinical translation is hampered by a cascade of physiological barriers spanning the airway mucus layer, mucociliary clearance, alveolar macrophage uptake, cellular internalization, and endosomal sequestration. In this review, we adopt a barrier-oriented framework to systematically dissect these extracellular, cellular, and intracellular obstacles, highlighting how disease-specific microenvironments further modulate delivery efficiency. We then critically examine emerging engineering strategies-including nanocarrier surface modifications, biomimetic vesicles, aerosol optimization, and stimuli-responsive formulations that are designed to overcome these barriers. Integrating mechanistic insights with disease-specific considerations, we analyze how distinct pulmonary pathologies necessitate tailored delivery solutions, emphasizing that successful translation requires coupling nanoengineering with the unique cellular and molecular landscapes of target tissues. Finally, we discuss translational challenges, including manufacturing scalability, long-term safety, and regulatory constraints, and outline emerging solutions that may enable next-generation inhaled nucleic acid therapies. By providing a synthesis of barrier-oriented design principles and disease-driven targeting strategies, this review offers a comprehensive roadmap for accelerating the clinical adoption of inhaled nucleic acid therapeutics.
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BibTeX
@article{yu2026inhaled,
title = {{Inhaled nucleic acid therapeutics for respiratory diseases: delivery barriers, translational challenges, and emerging solutions.}},
author = {Leijie Yu and Chongrui Zhou and Xiang Cheng and Xia Zhao and Xingru Yi and Yaqin Tang and Keyu Su and Fangyu Qiao and Jing Xie and Robert J Lee},
journal = {Precision clinical medicine},
year = {2026},
month = oct,
doi = {10.1093/pcmedi/pbag030},
url = {https://europepmc.org/article/MED/43011863},
note = {CC BY-NC},
}
RIS
TY - JOUR
TI - Inhaled nucleic acid therapeutics for respiratory diseases: delivery barriers, translational challenges, and emerging solutions.
AU - Leijie Yu
AU - Chongrui Zhou
AU - Xiang Cheng
AU - Xia Zhao
AU - Xingru Yi
AU - Yaqin Tang
AU - Keyu Su
AU - Fangyu Qiao
AU - Jing Xie
AU - Robert J Lee
PY - 2026
DA - 2026/10/24
JO - Precision clinical medicine
DO - 10.1093/pcmedi/pbag030
UR - https://europepmc.org/article/MED/43011863
AB - Pulmonary delivery of nucleic acid therapeutics represents a transformative strategy for treating a broad spectrum of respiratory diseases, including lung cancer, pulmonary fibrosis, chronic obstructive pulmonary disease, and acute lung injury. Despite their promise, effective clinical translation is hampered by a cascade of physiological barriers spanning the airway mucus layer, mucociliary clearance, alveolar macrophage uptake, cellular internalization, and endosomal sequestration. In this review, we adopt a barrier-oriented framework to systematically dissect these extracellular, cellular, and intracellular obstacles, highlighting how disease-specific microenvironments further modulate delivery efficiency. We then critically examine emerging engineering strategies-including nanocarrier surface modifications, biomimetic vesicles, aerosol optimization, and stimuli-responsive formulations that are designed to overcome these barriers. Integrating mechanistic insights with disease-specific considerations, we analyze how distinct pulmonary pathologies necessitate tailored delivery solutions, emphasizing that successful translation requires coupling nanoengineering with the unique cellular and molecular landscapes of target tissues. Finally, we discuss translational challenges, including manufacturing scalability, long-term safety, and regulatory constraints, and outline emerging solutions that may enable next-generation inhaled nucleic acid therapies. By providing a synthesis of barrier-oriented design principles and disease-driven targeting strategies, this review offers a comprehensive roadmap for accelerating the clinical adoption of inhaled nucleic acid therapeutics.
SN - 2096-5303
SN - 2516-1571
ER -