title: Bio-inspired pulmonary surfactant-modified nanogels: A promising siRNA delivery system.
abstract: Inhalation therapy with small interfering RNA (siRNA) is a promising approach in the treatment of pulmonary disorders. However, clinical translation is severely limited by the lack of suitable delivery platforms. In this study, we aim to address this limitation by designing a novel bioinspired hybrid nanoparticle with a core-shell nanoarchitecture, consisting of a siRNA-loaded dextran nanogel (siNG) core and a pulmonary surfactant (Curosurf®) outer shell. The decoration of siNGs with a surfactant shell enhances the colloidal stability and prevents siRNA release in the presence of competing polyanions, which are abundantly present in biofluids. Additionally, the impact of the surfactant shell on the biological efficacy of the siNGs is determined in lung cancer cells. The presence of the surfactants substantially reduces the cellular uptake of siNGs. Remarkably, the lowered intracellular dose does not impede the gene silencing effect, suggesting a crucial role of the pulmonary surfactant in the intracellular processing of the nanoparticles. In order to surmount the observed reduction in cellular dose, folate is incorporated as a targeting ligand in the pulmonary surfactant shell to incite receptor-mediated endocytosis. The latter substantially enhances both cellular uptake and gene silencing potential, achieving efficient knockdown at siRNA concentrations in the low nanomolar range.
authors: Laboratory for General Biochemistry and Physical Pharmacy, Faculty of Pharmacy, Ghent University, Ottergemsesteenweg 460, 9000 Ghent, Belgium. Electronic address: lynn.debacker@ugent.be.
authors: Lynn
authors: L
authors: De Backer
authors: Laboratory for General Biochemistry and Physical Pharmacy, Faculty of Pharmacy, Ghent University, Ottergemsesteenweg 460, 9000 Ghent, Belgium. Electronic address: kevin.braeckmans@ugent.be.
authors: Kevin
authors: K
authors: Braeckmans
authors: Department of Electron Microscopy, Groningen Biomolecular Sciences and Biotechnology Institute, University of Groningen, Nijenborgh 7, 9747 AG Groningen, The Netherlands. Electronic address: m.c.a.stuart@rug.nl.
authors: Marc C A
authors: MC
authors: Stuart
authors: Laboratory for General Biochemistry and Physical Pharmacy, Faculty of Pharmacy, Ghent University, Ottergemsesteenweg 460, 9000 Ghent, Belgium. Electronic address: jo.demeester@ugent.be.
authors: Jo
authors: J
authors: Demeester
authors: Laboratory for General Biochemistry and Physical Pharmacy, Faculty of Pharmacy, Ghent University, Ottergemsesteenweg 460, 9000 Ghent, Belgium. Electronic address: stefaan.desmedt@ugent.be.
authors: Stefaan C
authors: SC
authors: De Smedt
authors: Laboratory for General Biochemistry and Physical Pharmacy, Faculty of Pharmacy, Ghent University, Ottergemsesteenweg 460, 9000 Ghent, Belgium. Electronic address: koen.raemdonck@ugent.be.
authors: Koen
authors: K
authors: Raemdonck
mesh_terms: D002460:Cell Line; D045744:Cell Line, Tumor; D003911:Dextrans / Q000737:chemistry* / Q000378:metabolism; D004337:Drug Carriers / Q000737:chemistry / Q000378:metabolism; D016503:Drug Delivery Systems; D005782:Gels / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D008168:Lung / Q000166:cytology*; D011663:Pulmonary Surfactants / Q000737:chemistry* / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000008:administration & dosage* / Q000235:genetics
chemical_list: D003911:Dextrans; D004337:Drug Carriers; D005782:Gels; D011663:Pulmonary Surfactants; D034741:RNA, Small Interfering
keywords: Dextran nanogels; Hybrid nanoparticles; Lung; Pulmonary surfactant; Targeted delivery; siRNA delivery