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  3. Understanding excipient interactions unlocks untapped potential of RNA-lipid nanoparticles in dry powder formulations for local pulmonary delivery

Understanding excipient interactions unlocks untapped potential of RNA-lipid nanoparticles in dry powder formulations for local pulmonary delivery

  • J Control Release. 2025 Dec 12:390:114539. doi: 10.1016/j.jconrel.2025.114539.
Nora Martini 1,  Leonie Deßloch 2,  Taras Sych 3,  Otto Berninghausen 4,  J Merl-Pham 5,  Sjoerd Dijkstra 1,  Simone P Carneiro 6,  Marion Frankenberger 7,  Roland Beckmann 4,  Jürgen Behr 8,  Gabriele Matschiner 9,  Christine Schuberth-Wagner 9,  A Önder Yildirim 10,  David C Jürgens 11,  Erdinc Sezgin 3,  Olivia M Merkel 11,  Benjamin Winkeljann 12
Affiliations

Affiliations

  • 1 Department of Pharmacy, Comprehensive Pneumology Center (CPC-M), Ludwig-Maximilians-Universität München, Member of the German Center for Lung Research (DZL), 81377 Munich, Germany.
  • 2 Department of Pharmacy, Comprehensive Pneumology Center (CPC-M), Ludwig-Maximilians-Universität München, Member of the German Center for Lung Research (DZL), 81377 Munich, Germany; RNhale GmbH, Am Klopferspitz 19, 82152 Planegg, Germany.
  • 3 Science for Life Laboratory, Department of Women's and Children's Health, Karolinska Institutet, Solna, Sweden.
  • 4 Gene Center and Department of Biochemistry, University of Munich, Munich 81377, Germany.
  • 5 Metabolomics and Proteomics Core, Helmholtz Zentrum Munich, Ingolstaedter Landstr. 1, 85764 Neuherberg, Germany.
  • 6 Department of Pharmacy, Comprehensive Pneumology Center (CPC-M), Ludwig-Maximilians-Universität München, Member of the German Center for Lung Research (DZL), 81377 Munich, Germany; Center for NanoScience (CeNS), Ludwig-Maximilians-Universität München, Munich, Germany; Pharmaceutical Engineering and Technology Research Scientists (PETRS), Germany.
  • 7 Institute of Lung Health and Immunity (LHI) with CPC-M bioArchive, Comprehensive Pneumology Center (CPC-M), Helmholtz Munich, Member of the German Center for Lung Research (DZL), Munich, Germany.
  • 8 Department of Medicine V, LMU University Hospital, Comprehensive Pneumology Center (CPC-M), Ludwig-Maximilians-Universität München, Member of the German Center for Lung Research (DZL), Munich, Germany.
  • 9 RNhale GmbH, Am Klopferspitz 19, 82152 Planegg, Germany.
  • 10 Institute of Lung Health and Immunity (LHI) with CPC-M bioArchive, Comprehensive Pneumology Center (CPC-M), Helmholtz Munich, Member of the German Center for Lung Research (DZL), Munich, Germany; Institute of Experimental Pneumology, Ludwig-Maximilians University (LMU), Munich, Germany.
  • 11 Department of Pharmacy, Comprehensive Pneumology Center (CPC-M), Ludwig-Maximilians-Universität München, Member of the German Center for Lung Research (DZL), 81377 Munich, Germany; RNhale GmbH, Am Klopferspitz 19, 82152 Planegg, Germany; Center for NanoScience (CeNS), Ludwig-Maximilians-Universität München, Munich, Germany.
  • 12 Department of Pharmacy, Comprehensive Pneumology Center (CPC-M), Ludwig-Maximilians-Universität München, Member of the German Center for Lung Research (DZL), 81377 Munich, Germany; RNhale GmbH, Am Klopferspitz 19, 82152 Planegg, Germany; Center for NanoScience (CeNS), Ludwig-Maximilians-Universität München, Munich, Germany; Pharmaceutical Engineering and Technology Research Scientists (PETRS), Germany. Electronic address: [email protected].
PMID: 41391722 DOI: 10.1016/j.jconrel.2025.114539
Abstract

Small interfering RNA (siRNA)-loaded lipid nanoparticles (LNPs) are a promising modality for gene silencing therapies. Pulmonary delivery offers an attractive, non-invasive route to target respiratory diseases. However, the development of stable dry powder formulations suitable for inhalation remains a key challenge. In this study, we investigated the impact of spray drying on the physicochemical integrity and biological performance of siRNA-LNPs. Four LNP formulations differing in PEG-lipid helper lipid content were subjected to spray drying in the presence of a lactose matrix. The impact of formulation parameters on physicochemical integrity, colloidal stability, structural preservation, and biological behaviour was systematically evaluated before and after spray drying and predicted by molecular dynamic simulations. Choosing this holistic approach demonstrates that LNP composition critically influences suitability for spray drying and provides key insights for the development of stable pulmonary siRNA therapies.

Keywords

Lipid nanoparticles; Lung delivery; Molecular dynamic simulation; Mucus diffusion; Spray drying.

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