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. 2013 May 27;52(22):5757-61.
doi: 10.1002/anie.201209991. Epub 2013 Apr 22.

Supramolecular self-assembled nanoparticles mediate oral delivery of therapeutic TNF-α siRNA against systemic inflammation

Lichen Yin  1 , Ziyuan Song, Qiuhao Qu, Kyung Hoon Kim, Nan Zheng, Catherine Yao, Isthier Chaudhury, Haoyu Tang, Nathan P Gabrielson, Fatih M Uckun, Jianjun Cheng
Affiliations

Supramolecular self-assembled nanoparticles mediate oral delivery of therapeutic TNF-α siRNA against systemic inflammation

Lichen Yin et al. Angew Chem Int Ed Engl. .
No abstract available

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Figures

Figure 1
Figure 1
(A) Schematic illustration, (B) SEM image, and (C) particle size and zeta potential of SSNPs (bar = 200 nm in SEM image).
Figure 2
Figure 2
Intestinal absorption of Cy3-siRNA-containing SSNPs. (A) Papp of Cy3-siRNA across human non-FAE and FAE models (n = 3). (B) CLSM images showing cross-sections of the FAE model at 5-μm increments in the Z direction following SSNPs treatment for 4 h (bar = 20 μm). (C) Penetration depth of Cy3-siRNA in the FAE model. (D) TEER of the FAE model following incubation with SSNPs (n = 3). (E) CLSM images of the FAE model stained for ZO-1 after treatment with SSNPs (bar = 20 μm). (F) Uptake of SSNPs in the non-FAE model following 4-h incubation (n = 3). (G) Intestinal absorption pathways of SSNPs, including transcellular transport by M cells (pathway I), uptake by normal enterocytes (pathway II), and paracellular transport via transiently opened tight junctions (pathway III). The absorbed SSNPs were transferred either to GAMs or to systemic circulation.
Figure 3
Figure 3
SSNPs deliver TNF-α siRNA to macrophages via mannose receptor–mediated endocytosis and attenuate TNF-α production in vitro. (A) Uptake of Cy3-siRNA-containing SSNPs in RAW 264.7 cells following incubation for 4 h (n = 3). (B) Uptake of SSNPs in RAW 264.7 cells in the presence of various endocytosis inhibitors (n = 3). (C) CLSM images showing internalization of Cy3-siRNA-containing SSNPs in RAW 264.7 cells. Cy3-siRNA-SSNPs co-localized with FITC-CTB (D, white arrows) rather than with transferrin–Alexa Fluor 635 (E) (bar = 10 μm). TNF-α (F) and TNF-α mRNA levels (G) of RAW 264.7 cells following treatment with SSNPs at 0.1 μg siRNA/mL. (H) Comparison on the TNF-α knockdown efficiencies of SSNPs and LPF2000/siRNA complexes at various siRNA doses (n = 3).
Figure 4
Figure 4
Orally delivered SSNPs mediate efficient RNAi against LPS-induced TNF-α production and protected mice from acute hepatic injury. (A) Biodistribution of DY800-siRNA 2 h post oral gavage of SSNPs or naked DY800-siRNA (n = 3). (B) Serum TNF-α level of mice gavaged with SSNPs at 200 μg siRNA/kg (n = 6). (C) Relative TNF-α mRNA levels in mouse liver, spleen, and lung 24 h after oral gavage of SSNPs (n = 3). (D) Serum ALT and AST levels of mice 5 h after LPS/D-GalN stimulation (n = 4). (E) Survival of mice following oral gavage of SSNPs and i.p. injection of LPS/D-GalN 24 h later (n = 10). (F) HE-stained liver sections from mice 5 h after LPS/D-GalN stimulation (bar = 1 mm).
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