2. Academic Validation
  3. Pulmonary Delivery of siRNA Anti-TNFα-loaded Lipid Nanoparticles for Rapid Recovery in Murine Acute Lung Injury

Pulmonary Delivery of siRNA Anti-TNFα-loaded Lipid Nanoparticles for Rapid Recovery in Murine Acute Lung Injury

  • Adv Healthc Mater. 2025 Aug 7:e00695. doi: 10.1002/adhm.202500695.
Qinglin Wang 1,  Jihana Achour 1 2,  Laila Emam 2 3 4,  Younes Louaguenouni 1,  Catherine Cailleau 1,  Françoise Mercier-Nomé 5,  Séverine Domenichini 6,  Claudine Delomenie 7,  Sezen Gul 1,  Juliette Vergnaud 1,  Nicolas Tsapis 1 2,  Arnaud Mansart 2 3 4,  Djillali Annane 2 3 4,  Francois Fay 1 2 8,  Elias Fattal 1 2
Affiliations

Affiliations

  • 1 Université Paris-Saclay, CNRS, Institut Galien Paris-Saclay, Orsay, 91400, France.
  • 2 IHU-SEPSIS, Comprehensive Sepsis Center, Raymond Poincaré Hospital (AP-HP), University of Versailles Saint-Quentin en Yvelines, University Paris Saclay, Garches, 92380, France.
  • 3 General Intensive Care Unit, Raymond Poincaré Hospital (AP-HP), University of Versailles Saint-Quentin en Yvelines, University Paris Saclay, Garches, 92380, France.
  • 4 Université Paris-Saclay, UVSQ, INSERM, U1173 2I, Montigny-le-Bretonneux, 78180, France.
  • 5 UMS-IPSIT Plateforme PHIC, Université Paris-Saclay, CNRS, Inserm, Ingénierie et Plateformes au Service de l'Innovation Thérapeutique, Orsay, France.
  • 6 UMS-IPSIT Plateforme MIPSIT, Université Paris-Saclay, CNRS, Inserm, Ingénierie et Plateformes au Service de l'Innovation Thérapeutique, Orsay, France.
  • 7 UMS-IPSIT Plateforme ACTAGEN, Université Paris-Saclay, CNRS, Inserm, Ingénierie et Plateformes au Service de l'Innovation Thérapeutique, Orsay, France.
  • 8 Institut Universitaire de France (IUF), France.
PMID: 40776451 DOI: 10.1002/adhm.202500695
Abstract

This study investigates the potential of pulmonary delivery of siRNA as an emergency therapy for acute lung injury (ALI). To obtain a quick anti-inflammatory response, TNF-α, a critical pro-inflammatory cytokine, is knocked down for its early involvement in inflammatory responses. Therefore, TNF-α siRNA-lipid nanoparticles (LNPs) are designed and characterized for cellular uptake in lipopolysaccharide (LPS)-activated RAW264.7 murine macrophages, primary alveolar macrophages, and neutrophils from a murine ALI model. Intracellular trafficking and siRNA cytoplasmic release are evaluated in untreated and LPS-activated RAW264.7 cells. LPS-activated cells exhibit a fast and strong uptake of LNPs, including in primary cells. In RAW264.7 cells, significant endosomal escape and siRNA cytoplasmic release are observed after 16 h. In vitro efficacy studies reveal consistent TNF-α inhibition across pre-, co-, and post-incubation protocols, confirming the versatility of siRNA-LNPs in preventive or curative conditions. After intratracheal administration of TNF-α siRNA-LNPs in a murine ALI model, the distribution of LNPs demonstrates an accumulation in immune cells, including macrophages and neutrophils, reducing TNF-α and IL-6 levels, indicating a rapid anti-inflammatory effect. This work underscores the efficacy of TNF-α siRNA-LNPs in treating lung inflammatory diseases like ALI and highlights the importance of optimizing LNP distribution and delivery timing to enhance therapeutic outcomes.

Keywords

TNF‐α; acute lung injury; lung delivery; nanomedicine; siRNA.

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