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. 2022 Jul 18:10:939312.
doi: 10.3389/fbioe.2022.939312. eCollection 2022.

Nanoscale Porphyrin Metal-Organic Frameworks Deliver siRNA for Alleviating Early Pulmonary Fibrosis in Acute Lung Injury

Changmei Weng  1 , Guanhua Li  1 , Dongdong Zhang  1 , Zhaoxia Duan  1 , Kuijun Chen  1 , Jieyuan Zhang  1 , Tao Li  2   3 , Jianmin Wang  1
Affiliations

Nanoscale Porphyrin Metal-Organic Frameworks Deliver siRNA for Alleviating Early Pulmonary Fibrosis in Acute Lung Injury

Changmei Weng et al. Front Bioeng Biotechnol. .

Abstract

Acute lung injury (ALI) has high mortality and still lacks novel and efficient therapies. Zinc finger E-box binding homeobox 1 and 2 (ZEB1/2) are highly expressed in the early stage of ALI and are positively correlated with the progression of pulmonary fibrosis. Herein, we developed a nanoscale Zr(IV)-based porphyrin metal-organic (ZPM) framework to deliver small interfering ZEB1/2 (siZEB1/2) to alleviate early pulmonary fibrosis during ALI. This pH-responsive nano-ZPM system could effectively protect siRNAs during lung delivery until after internalization and rapidly trigger siRNA release under the mildly acidic environment of the endo/lysosome (pH 4.0-6.5) for transfection and gene silencing. Furthermore, the in vivo studies confirmed that this nano-ZPM system could anchor in inflamed lungs. Moreover, the ZEB1/2 silencing led to increased E-cadherin and decreased α-SMA levels. Overall, the nano-ZPM system was an excellent non-viral vector system to deliver siRNAs to alleviate early pulmonary fibrosis during ALI.

Keywords: endosomal escape; non-viral vector; porphyrin metal-organic framework; pulmonary fibrosis; siRNA.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

SCHEME 1
SCHEME 1
(A) The scheme for ZPM@PDE-siZEB1/2 preparation and (B) intratracheal therapeutic mechanism of ZPM@PDE-siZEB1/2 in ALI model mice.
SCHEME 2
SCHEME 2
The synthetic scheme of PDEA-bPEI (PDE).
FIGURE 1
FIGURE 1
(A,B) TEM of TZM and TZM@PDE, (C) Hydrodynamic size distribution, (D) Zeta potential, and (E) Photographs of TZM and TZM@PDE in aqueous solutions.
FIGURE 2
FIGURE 2
(A) Fourier transform infrared (FT-IR) spectra, (B) TG weight loss profiles, (C) XRD patterns of PDE, ZPM, and ZPM@PDE, (D) HR-TEM and elemental mapping images of ZPM@PDE, (E) N2 adsorption-desorption isotherms and DFT pore size distribution of ZPM, and (F) Hydrodynamic size distribution and PDI of ZPM in H2O for 5 days.
FIGURE 3
FIGURE 3
(A) Gel retardation assay of ZPM@PDE/siZEB1/2 with different mass ratio, (B) siZEB1/2 release from ZPM@PDE-siZEB1/2 at pH 5.0 or pH 7.4 over time, (C) Cytotoxicity of PDE@siZEB1/2 and ZPM@PDE-siZEB1/2, (D) Uptake of ZPM@PDE-Cy5-siZEB1/2 (red) in vitro. Nuclei stained with DAPI nuclear dye (blue), and (E) Silencing efficacy of ZPM@PDE-siZEB1/2 in vitro. (n = 3, *p < 0.05, **p < 0.01, ***p < 0.001). For each group: Ⅰ, Control; Ⅱ, Naked CY5-siZEB1/2; Ⅲ, Lip 2000-CY5-siZEB1/2; Ⅳ, ZPM@PDE-CY5-siZEB1/2 (pH 5.0); Ⅴ, ZPM@PDE-CY5-siZEB1/2 (pH 7.4).
FIGURE 4
FIGURE 4
(A) Fluorescent images of lungs, (B) Uptake of CY5-siZEB1/2 (red) in mice, and (C) The relative fluorescence intensity of CY5. Nuclei stained with DAPI nuclear dye (blue). For each group: Ⅰ, Control; Ⅱ, LPS + Naked CY5-siZEB1/2; Ⅲ, LPS + ZPM@PDE-CY5-siZEB1/2.
FIGURE 5
FIGURE 5
The histopathological change of lung tissues. (A) Macroscopic appearance of lungs, (B,C) H&E and Masson’s trichrome staining of lungs; (D) pulmonary injury score (Smith score); and (E) pulmonary fibrosis score (Aschoff score) from mice treated with saline (control), LPS, LPS + Naked siZEB1/2 and LPS + ZPM@PDE-siZEB1/2. (*p < 0.05, **p < 0.01, ***p < 0.001). For each group:Ⅰ, Control; Ⅱ, LPS; Ⅲ, LPS + Naked siZEB1/2; Ⅳ, LPS + ZPM@PDE-siZEB1/2.
FIGURE 6
FIGURE 6
Effects of ZPM@PDE-siZEB1/2 on the expression of E-cadherin and α-SMA in mice. (A) Immunofluorescence assays expression of E-cadherin (green) and α-SMA protein (red), nuclei stained with DAPI nuclear dye (blue), (B,C) The relative fluorescence unit (RFU) of E-cadherin and α-SMA, (D) Immunohistochemical analysis expression, and (E) The relative staining intensity of E-cadherin and α-SMA. (*p < 0.05, **p < 0.01, ***p < 0.001). For each group:Ⅰ, Control; Ⅱ, LPS; Ⅲ, LPS + Naked siZEB1/2; Ⅳ, LPS + ZPM@PDE-siZEB1/2.
FIGURE 7
FIGURE 7
Effects of ZEB1/2 silencing ability in vivo. (A) Immunohistochemical analysis expression of ZEB1/2 in mice lungs, (B) expression of ZEB1/2 were detected by quantitative RT-PCR, and (C,D) western blot analysis. (*p < 0.05, **p < 0.01, ***p < 0.001). For each group:Ⅰ, Control; Ⅱ, LPS + Naked siZEB1/2; Ⅲ, LPS + ZPM@PDE-siZEB1/2.
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