2. Academic Validation
  3. Lipid nanoparticles target neutrophils to reduce SARS-CoV-2-induced lung injury and inflammation

Lipid nanoparticles target neutrophils to reduce SARS-CoV-2-induced lung injury and inflammation

  • J Control Release. 2025 Jun 10:382:113736. doi: 10.1016/j.jconrel.2025.113736.
Ha Eun Shin 1,  Stefanos Giannakopoulos 1,  Joo Dong Park 2,  Hye Jung Jang 2,  Chun Gwon Park 3,  Sean V Murphy 4,  Juwon Park 5,  Saguna Verma 6,  Wooram Park 7
Affiliations

Affiliations

  • 1 Department of Tropical Medicine, Medical Microbiology, and Pharmacology, John A. Burns School Medicine, University of Hawai'i at Manoa, Honolulu, HI 96813, USA.
  • 2 Department of Integrative Biotechnology, College of Biotechnology and Bioengineering Sungkyunkwan University (SKKU), Suwon, Gyeonggi 16419, Republic of Korea.
  • 3 Department of Biomedical Engineering and Department of Intelligent Precision Healthcare Convergence, Institute for Cross-disciplinary Studies (ICS), SKKU, Suwon, Gyeonggi 16419, Republic of Korea.
  • 4 Wake Forest Institute for Regenerative Medicine, Wake Forest School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157, USA.
  • 5 Department of Tropical Medicine, Medical Microbiology, and Pharmacology, John A. Burns School Medicine, University of Hawai'i at Manoa, Honolulu, HI 96813, USA. Electronic address: jpark25@hawaii.edu.
  • 6 Department of Tropical Medicine, Medical Microbiology, and Pharmacology, John A. Burns School Medicine, University of Hawai'i at Manoa, Honolulu, HI 96813, USA. Electronic address: saguna@hawaii.edu.
  • 7 Department of Integrative Biotechnology, College of Biotechnology and Bioengineering Sungkyunkwan University (SKKU), Suwon, Gyeonggi 16419, Republic of Korea; Department of MetaBioHealth, ICS, SKKU, Suwon, Gyeonggi 16419, Republic of Korea. Electronic address: parkwr@skku.edu.
PMID: 40254136 DOI: 10.1016/j.jconrel.2025.113736
Abstract

The need to understand key players driving pulmonary inflammation and fibrosis in COVID-19 patients leading to effective preventive strategies is imminent. Excessive neutrophil activation, including extracellular trap (NET) formation, is associated with severe COVID-19 and long-term sequelae. However, the clinical applications of neutrophil-targeting therapies are challenging due to short bioavailability and lack of cell-type specificity. This study presents a lipid nanoparticle (LNP) platform designed to deliver two established NET inhibitors, DNase I and Sivelestat (Siv) referred to as DPNLNPs, specifically to lung neutrophils. In vitro and in vivo experiments demonstrate that DPNLNPs preferentially accumulate in the lung neutrophils and degrade NETs as efficiently as the free DNase I and Siv. Additionally, administration of DPNLNPs in K18-hACE2 mice significantly inhibited SARS-CoV-2-induced NETs at a much lower dose than the free drugs and correlated with reduced lung and systemic inflammation, lung epithelium injury, and Collagen deposition. Importantly, DPNLNP treatment only during the symptomatic phase of Infection improved SARS-CoV-2 outcome revealing the complex role of NETs in COVID-19 pathogenesis. Together, this study serves as a proof-of-concept for adapting the LNP platform to deliver more than one immunomodulatory drug in a cell-specific manner to manage NET-associated complications in COVID-19 and Other respiratory diseases.

Keywords

DNase I; Lipid nanoparticle (LNP); Lung injury and K18-hACE2 mice; Neutrophil elastase, SARS-CoV-2; Neutrophil extracellular trap (NET); Precision-targeting nanoparticle.

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