Development of inhalable dry powders with a high content of naked cholesterol-modified siRNA by spray freeze drying and spray drying techniques.

Authors

Tomoyuki Okuda, Kotone Oshiro, Mayu Sakakibara, Takashi Murakami, Hirokazu Okamoto

Published in

International journal of pharmaceutics. Pages 127308. Aug 11, 2026. Epub Aug 11, 2026.

Abstract

Inhaled dry powder formulations of naked small interfering RNA (siRNA), even those without a transfection reagent, are promising in clinical applications for respiratory diseases. We herein attempted to newly produce inhalable spray-freeze-dried (SFD) and spray-dried (SD) powders mainly composed of naked siRNA and leucine, an excipient, at a high siRNA content of 10 or 20% (w/w) in order to examine the effects of a cholesterol (Chol) modification to siRNA on their physical and biological properties. The Chol modification to siRNA improved the aerosol performance of the SD powder, but not the SFD powder, even though it did not significantly change the particle structures of these powders. Irrespective of the content of or Chol modification to siRNA, the SFD powder exhibited excellent aerosol performance with a high fine particle fraction of >64%. The structural and biological integrities of siRNA were almost completely maintained in the SFD and SD powders regardless of the content of or Chol modification to siRNA, while powders loading naked Chol-modified siRNA, unlike those loading naked non-modified siRNA, attained gene silencing against cultured cancer cells even without a transfection reagent. After their intratracheal administration to mice, the SFD and SD powders loading naked Chol-modified siRNA both achieved gene silencing against cancer cells metastasized in the lungs and did not significantly affect any of the following toxicity indices: body weight, the arterial oxygen saturation level, lung weight, or the number of nucleated cells and amounts of lactate dehydrogenase and tumor necrosis factor in bronchoalveolar lavage fluid.

PMID:
42580499
Bibliographic data and abstract were imported from PubMed on 12 Aug 2026.

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