Surfactant Protein B promotes cytosolic SiRNA delivery by adopting a Virus-like mechanism of action



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Guagliardo, Roberta and Herman, Lore and Penders, Jelle and Zamborlin, Agata and Keersmaecker, Herlinde de and Van de Vyver, Thijs and Verstraeten, Sandrine and Merckx, Pieterjan and Mingeot-Leclercq, Marie-Paule and Echaide Torreguitar, Mercedes and Pérez Gil, Jesús and Stevens, Molly M. and De Smedt, Stefaan and Raemdonck, Koen (2021) Surfactant Protein B promotes cytosolic SiRNA delivery by adopting a Virus-like mechanism of action. ACS Nano, 15 (5). pp. 8095-8109. ISSN 1936-0851; Electronic: 1936-086X

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RNA therapeutics are poised to revolutionize medicine. To unlock the full potential of RNA drugs, safe and efficient (nano)formulations to deliver them inside target cells are required. Endosomal sequestration of nanocarriers represents a major bottleneck in nucleic acid delivery. Gaining more detailed information on the intracellular behavior of RNA nanocarriers is crucial to rationally develop delivery systems with improved therapeutic efficiency. Surfactant protein B (SPB) is a key component of pulmonary surfactant (PS), essential for mammalian breathing. In contrast to the general belief that PS should be regarded as a barrier for inhaled nanomedicines, we recently discovered the ability of SP-B to promote gene silencing by siRNA-loaded and lipid-coated nanogels. However, the mechanisms governing this process are poorly understood. The major objective of this work was to obtain mechanistic insights into the SP-B-mediated cellular delivery of siRNA. To this end, we combined siRNA knockdown experiments, confocal microscopy, and focused ion beam scanning electron microscopy imaging in an in vitro non-small-cell lung carcinoma model with lipid mixing assays on vesicles that mimic the composition of (intra)cellular membranes. Our work highlights a strong correlation between SP-B-mediated fusion with anionic endosomal membranes and cytosolic siRNA delivery, a mode of action resembling that of certain viruses and virus-derived cell-penetrating peptides. Building on these gained insights, we optimized the SP-B proteolipid composition, which dramatically improved delivery efficiency. Altogether, our work provides a mechanistic understanding of SP-B-induced perturbation of intracellular membranes, offering opportunities to fuel the rational design of SP-B-inspired RNA nanoformulations for inhalation therapy.

Item Type:Article
Uncontrolled Keywords:Nanomedicine; siRNA; Cellular delivery; Pulmonary surfactant; Nano−bio interface; Endosomal escape
Subjects:Medical sciences > Biology > Molecular biology
Medical sciences > Biology > Biochemistry
ID Code:67972
Deposited On:27 Sep 2021 14:30
Last Modified:04 Apr 2022 14:57

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