RT Journal Article
T1 Surfactant protein B-derived peptides as endosomal escape enhancers for pulmonary delivery of siRNA
A1 Herman, Lore
A1 Guagliardo, Roberta
A1 Zamborlin, Agata
A1 Liu, Qiaoyu
A1 Pérez Gil, Jesús
A1 De Smedt, Stefaan C.
A1 Raemdonck, Koen
AB Respiratory diseases still cause significant mortality and morbidity worldwide, highlighting the need for new inhalable drugs. RNA therapeutics, which have the potential to modulate the expression of virtually any gene, could address this unmet medical need. Nevertheless, clinical translation requires the design of RNA formulations able to overcome the extra- and intracellular barriers in the lung. We previously discovered that the endogenous cationic amphiphilic surfactant protein B (SP-B) promotes cytosolic delivery of small interfering RNA (siRNA) in lung-related cell types via endosomal membrane fusion. However, to bypass drawbacks related to the use of animal-derived SP-B, there is a keen interest in developing synthetic SP-B analogues with comparable activity. Here, we show that native SP-B can successfully be replaced by smaller peptides, with the N-terminal heptapeptide and amphipathic helix being minimally required to promote siRNA-induced gene silencing. Peptidolipid-coated nanogels were designed and demonstrated equivalent siRNA delivery efficacy compared to state-of-the-art lipid nanoparticles (LNPs). Moreover, they exhibit enhanced resistance to vibrating mesh nebulization and reduced inflammatory activation of bronchial epithelial cells. Collectively, the discovery of SP-B peptides as RNA delivery enhancers holds promise for developing potent inhalable RNA formulations with favorable safety profiles, of value for the treatment of chronic inflammatory pathologies.
PB Elsevier
SN 0168-3659
YR 2025
FD 2025
LK https://hdl.handle.net/20.500.14352/119249
UL https://hdl.handle.net/20.500.14352/119249
LA eng
NO Herman, L., Guagliardo, R., Zamborlin, A., Liu, Q., Pérez-Gil, J., De Smedt, S. C., & Raemdonck, K. (2025). Surfactant protein B-derived peptides as endosomal escape enhancers for pulmonary delivery of siRNA. Journal of Controlled Release, 381, 113571. https://doi.org/10.1016/j.jconrel.2025.02.067
NO L.H. acknowledges the Research Foundation-Flanders (grant 1S56121N; FWO, Belgium). K.R. has received funding from the European Research Council (ERC) under the European Union's Horizon 2020 research and innovation programme (Grant Agreement 101002571, RESPIRNA). Financial support from the Ghent University Special Research Fund is gratefully acknowledged (BOF12/GOA/014 and BOF19/GOA/008). J. P.-G. acknowledges funding from the Spanish Ministry of Science and Innovation (PID2021-124932OB-100) and the Regional Government of Madrid (P2018/NMT-4389).
NO Research Foundation Flanders
NO European Commission
NO Ghent University
NO Comunidad de Madrid
DS Docta Complutense
RD 18 dic 2025