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. 2024 Jul 3;24(26):8080-8088.
doi: 10.1021/acs.nanolett.4c01854. Epub 2024 Jun 18.

Lung-Specific mRNA Delivery Enabled by Sulfonium Lipid Nanoparticles

David O Popoola  1 , Zhi Cao  1 , Yuqin Men  1 , Xinyuan Li  1 , Mariano Viapiano  2 , Stephan Wilkens  3 , Juntao Luo  1 , Yong Teng  4 , Qinghe Meng  5 , Yamin Li  1
Affiliations

Lung-Specific mRNA Delivery Enabled by Sulfonium Lipid Nanoparticles

David O Popoola et al. Nano Lett. .

Abstract

Among various mRNA carrier systems, lipid nanoparticles (LNPs) stand out as the most clinically advanced. While current clinical trials of mRNA/LNP therapeutics mainly address liver diseases, the potential of mRNA therapy extends far beyond─yet to be unraveled. To fully unlock the promises of mRNA therapy, there is an urgent need to develop safe and effective LNP systems that can target extrahepatic organs. Here, we report on the development of sulfonium lipid nanoparticles (sLNPs) for systemic mRNA delivery to the lungs. sLNP effectively and specifically delivered mRNA to the lungs following intravenous administration in mice. No evidence of lung and systemic inflammation or toxicity in major organs was induced by sLNP. Our findings demonstrated that the newly developed lung-specific sLNP platform is both safe and efficacious. It holds great promise for advancing the development of new mRNA-based therapies for the treatment of lung-associated diseases and conditions.

Keywords: Sulfonium lipid nanoparticle; genome engineering; lung targeting; mRNA delivery; pulmonary endothelium.

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Conflict of interest statement

Conflict of Interest

A patent application for the lipid materials developed in this study has been filed by the State University of New York.

Figures

Figure 1.
Figure 1.
Sulfonium lipid nanoparticle (sLNP)-enabled systemic delivery of mRNA to the lungs. (A) Schematic illustration of the chemical structures of sulfonium lipids (DHSEH and DOSEH), the self-assembly process of mRNA-loaded sLNP (mRNA/sLNP), and the targeted delivry of mRNA to the lungs in mice. (B) Representative in vivo whole-body bioluminescence images of mice treated with PBS, free fLuc mRNA, and mRNA/sLNPs. (C) Representative ex vivo bioluminescence images of mouse organs. (D) Quantification of total bioluminescence flux from the lungs of mice treated with PBS, free mRNA, and mRNA-loaded LNPs. Data are presented as mean ± s.e.m., n = 3. (E) Percentage of background-subtracted bioluminescence signal originating from each organ in mice treated with mRNA-loaded LNPs.
Figure 2.
Figure 2.
Distribution of protein expression and kinetics study of mRNA/sLNP. (A) Schematic illustration of mouse lung lobes. (B) Representative ex vivo bioluminescence images of dissected lung lobes. (C) Quantification of average radiance for all five lung lobes. Data are presented as mean ± s.d., n = 3, one-way ANOVA analysis. (D) Whole-body bioluminescence images and (E) quantification of total flux at different time points for high (0.4 mg/kg) and low doses (0.1 mg/kg). Data are presented as mean ± s.d., n = 3. (F) The area under the curve (AUC) analysis shows cumulative bioluminescence.
Figure 3.
Figure 3.
sLNP-mediated mRNA delivery for genome engineering in the mouse lungs. (A) Schematic illustration of Cre-Lox recombination and tdTomato activation in Ai14 mouse following successful Cre mRNA delivery. (B) Representative ex vivo fluorescence images of lungs. (C) Representative confocal images and (D) quantification of tdTomato-positive cells per field of view (FOV) of lung slices obtained from mice received PBS, Cre mRNA/sLNP, or Cre mRNA/MC3-DOTAP. Scale bar = 100 μm. (E) Flow cytometry quantification of tdTomato-positive cells within lung endothelial, epithelial, and immune cell populations. Data are presented as mean ± s.d., n = 3, two-tailed unpaired t-test.
Figure 4.
Figure 4.
Proteomics analysis of sLNP protein corona. (A) Top 10 most abundant proteins on corona. The enriched proteins on the corona were categorized based on their (B) isoelectric point, (C) molecular weight, and (D) biological function.
Figure 5.
Figure 5.
sLNP does not induce inflammation or toxicity in mice. (A) Representative images of cells collected in BALF. (B) Quantification of macrophage counts, (C) variations in cytokine levels, and (D) total protein concentration in BALF. Cell counts of (E) red blood cell (RBC) and (F) white blood cell (WBC). Quantification of (G) AST and (H) BUN in serum. Data are presented as mean ± s.d., n = 3, two-tailed unpaired t-test. (I) H&E staining images of major organ slices. Scale bar = 100 μm.
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