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. 2024 Jun;14(6):2732-2747.
doi: 10.1016/j.apsb.2024.02.008. Epub 2024 Feb 12.

Gas-propelled nanomotors alleviate colitis through the regulation of intestinal immunoenvironment-hematopexis-microbiota circuits

Bo Xiao  1   2 , Yuqi Liang  2 , Ga Liu  2 , Lingshuang Wang  2 , Zhan Zhang  3   4 , Libin Qiu  2 , Haiting Xu  2 , Sean Carr  4   5 , Xiaoxiao Shi  2 , Rui L Reis  6 , Subhas C Kundu  6 , Zhenghua Zhu  1
Affiliations

Gas-propelled nanomotors alleviate colitis through the regulation of intestinal immunoenvironment-hematopexis-microbiota circuits

Bo Xiao et al. Acta Pharm Sin B. 2024 Jun.

Erratum in

Abstract

The progression of ulcerative colitis (UC) is associated with immunologic derangement, intestinal hemorrhage, and microbiota imbalance. While traditional medications mainly focus on mitigating inflammation, it remains challenging to address multiple symptoms. Here, a versatile gas-propelled nanomotor was constructed by mild fusion of post-ultrasonic CaO2 nanospheres with Cu2O nanoblocks. The resulting CaO2-Cu2O possessed a desirable diameter (291.3 nm) and a uniform size distribution. It could be efficiently internalized by colonic epithelial cells and macrophages, scavenge intracellular reactive oxygen/nitrogen species, and alleviate immune reactions by pro-polarizing macrophages to the anti-inflammatory M2 phenotype. This nanomotor was found to penetrate through the mucus barrier and accumulate in the colitis mucosa due to the driving force of the generated oxygen bubbles. Rectal administration of CaO2-Cu2O could stanch the bleeding, repair the disrupted colonic epithelial layer, and reduce the inflammatory responses through its interaction with the genes relevant to blood coagulation, anti-oxidation, wound healing, and anti-inflammation. Impressively, it restored intestinal microbiota balance by elevating the proportions of beneficial bacteria (e.g., Odoribacter and Bifidobacterium) and decreasing the abundances of harmful bacteria (e.g., Prevotellaceae and Helicobacter). Our gas-driven CaO2-Cu2O offers a promising therapeutic platform for robust treatment of UC via the rectal route.

Keywords: Anti-inflammation; Blood coagulation; Hematopexis; Immune regulation; Microbiota rebalance; Nanomotor; Rectal administration; Ulcerative colitis.

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Conflict of interest statement

The authors have no conflicts of interest to declare.

Figures

Image 1
Graphical abstract
Scheme 1
Scheme 1
Schematic diagram of CaO2–Cu2O as gas-driven nanomotors for effective treatment of UC through mucus penetration, colitis mucosa accumulation, ROS/RNS scavenging, down-regulation of inflammatory reaction, blood coagulation, wound healing, and intestinal microbiota modulation after rectal administration.
Figure 1
Figure 1
Fabrication and physicochemical characterization of CaO2–Cu2O. (A) Schematic diagram of the synthetic processes of CaO2–Cu2O. (B) SEM image and (C) hydrodynamic size distribution of CaO2–Cu2O. The scale bar represents 200 nm. (D) Distribution of elements in CaO2–Cu2O, which were examined by EDS analysis. The scale bar represents 100 nm. (E) The whole spectrum of CaO2–Cu2O by XPS analysis. (F) Trolox-equivalent anti-oxidative capacity of CaO2 and CaO2–Cu2O with different NP concentrations (10, 20, 40, and 80 mg/mL). (G) H2O2 and (H) O2•– scavenging capacities of CaO2–Cu2O with different Cu concentrations (50, 100, 150, 200, and 250 ng/mL). (I) SOD-like activity of CaO2–Cu2O with different Cu concentrations (200, 400, 600, 800, and 1000 ng/mL). Data are expressed as means ± SEM (n = 3).
Figure 2
Figure 2
In vitro anti-inflammatory and anti-oxidative activities of CaO2–Cu2O. (A) The secreted amounts of TNF-α from Raw 264.7 macrophages receiving the treatment of CaO2 and CaO2–Cu2O at an equal NP concentration. The secreted amounts of (B) TNF-α, (C) IL-6, and (D) IL-12 from Raw 264.7 macrophages with the treatment of CaO2–Cu2O at different Cu concentrations (100, 200, 400, and 800 ng/mL). Raw 264.7 macrophages without LPS stimulation were treated as a negative control, whereas LPS (1.0 μg/mL)-stimulated Raw 264.7 macrophages were treated as a positive control. Fluorescence images and mean fluorescence intensities of intracellular (E, F) ROS and (G, H) RNS in Raw 264.7 macrophages were detected by two fluorescence probes (DCFH-DA and DAF-FM-DA) after treatment with various NPs. The scale bar represents 20 μm. Flow cytometric histograms of the fluorescence intensities and the corresponding quantitative results of intracellular (I–K) ROS or (L–N) RNS after treatment with various NPs. Data are expressed as means ± SEM (n = 3; ∗P < 0.05, ∗∗P < 0.01, and ∗∗∗P < 0.001).
Figure 3
Figure 3
Hemostatic activity, mucus penetration, and colonic accumulation of CaO2–Cu2O. (A) Images of the hemorrhage symptom in the tail cutting test after treatment with different NPs for 30, 60, and 120 s, respectively. (B) Images of blood collecting tubes from mice receiving the treatment of CaO2 and CaO2–Cu2O. (C) Blood loss amounts and (D) hemostasis time of various experimental groups. Data are expressed as means ± SEM (n = 4; ∗P < 0.05, ∗∗P < 0.01, and ∗∗∗P < 0.001). (E) Schematic diagram of mucus penetration profiles of CaO2 and CaO2–Cu2O. The reaction equation of CaO2 and H2O is presented in the illustration. (F) Concentrations of dissolved O2 in CaO2 and CaO2–Cu2O suspensions after incubation for 180 s. Data are expressed as means ± SEM (n = 3; ∗P < 0.05, ∗∗P < 0.01, and ∗∗∗P < 0.001). (G) Mucus penetration profiles of CaO2 and CaO2–Cu2O. The scale bar represents 100 μm. (H) In vivo imaging of the GIT showing the bio-distribution of NPs after rectal administration. Once the NP suspensions were prepared, they were rectally administered to the mice at an equal Cou amount (2 mg/kg). (I) Accumulation profiles of CaO2@Cou and CaO2–Cu2O@Cou in the inflamed colon tissues. The scale bar represents 100 μm.
Figure 4
Figure 4
In vivo preventative effect of NPs against UC. (A) Schematic illustration of the experimental protocol. Mice were treated with DSS-contained water (3.5%, w/v) for 9 days and rectally administered with CaO2 and CaO2–Cu2O on Days 2, 5, and 8, respectively. (B) Variations of body weights over time, normalized to the percentage of the day-zero body weight. (C) DAI values, (D) colon lengths, (E) spleen weights, and (F) MPO activities of various experimental groups. The amounts of pro-inflammatory cytokines in the serum: (G) TNF-α, (H) IL-6, and (I) IL-10. Data are expressed as means ± SEM (n = 4; ∗P < 0.05, ∗∗P < 0.01, and ∗∗∗P < 0.001). (J) H&E− and PAS-stained colon tissues. The scale bar represents 20 μm. (K) Histological scores and (L) PAS staining areas of the colon tissues. (M) Images of monocyte-derived immune cells and neutrophils in the colon tissues from different experimental groups by immunofluorescent staining. The scale bar represents 50 μm. (N, O) Quantitative results of neutrophils and monocyte-derived immune cells according to the mean fluorescence intensities by CLSM analysis. Blood coagulation indexes of the serum from various experimental groups in terms of (P) APTT and (Q) PT. Data are expressed as means ± SEM (n = 3; ∗P < 0.05, ∗∗P < 0.01, and ∗∗∗P < 0.001).
Figure 5
Figure 5
Analysis of intestinal microorganisms from various experimental groups. (A) Chao and (B) Shannon indexes on OUT levels. (C) PCoA analysis of the bacterial colony. The abundance of (D) Odoribacter, (E) Faecalibaculum, (F) Roseburia, (G) Phascolarctobacterium, (H) Bifidobacterium, (I) Alistipes, (J) Escherichia coli, (K) Prevotellaceae, and (L) Helicobacter in the feces from various experimental groups. Data are expressed as means ± SEM (n = 4; ∗P < 0.05, ∗∗P < 0.01, and ∗∗∗P < 0.001).
Figure 6
Figure 6
Gene expression profiles of the colon tissues from various experimental groups at the transcriptome level. (A) GO enrichment and (B) hierarchical clustering analysis. Expression of (C) Hub genes and (D, E) closely related genes in the colon tissues from various experimental groups. (F) Schematic diagram of the therapeutic mechanism of CaO2–Cu2O against UC. Data are expressed as means ± SEM (n = 3; ∗P < 0.05, ∗∗P < 0.01, and ∗∗∗P < 0.001).
Figure 7
Figure 7
In vivo therapeutic outcomes of various NPs against UC. (A) Schematic illustration of the experimental protocol. Mice were treated with DSS-contained water (4.5%, w/v) for 5 days. After that, mice were treated with CaO2 and CaO2–Cu2O every three days via rectal administration. (B) Variations of body weights over time, normalized to the percentage of the day-zero body weight. (C) DAI values, (D) colon lengths, (E) spleen weights, and (F) MPO activities of various experimental groups. Data are expressed as means ± SEM (n = 5–7; ∗P < 0.05, ∗∗P < 0.01, and ∗∗∗P < 0.001). The amounts of pro-inflammatory cytokines in the serum: (G) TNF-α, (H) IL-6, and (I) IL-10. Data are expressed as means ± SEM (n = 4; ∗P < 0.05, ∗∗P < 0.01, and ∗∗∗P < 0.001). (J) H&E-stained and PAS-stained colon tissues. The scale bar represents 20 μm. (K) Histological scores and (L) PAS staining areas of the colon tissues. (M) Images of monocyte-derived immune cells and neutrophils in the colon tissues from different experimental groups by immunofluorescent staining. The scale bar represents 50 μm. Quantitative results of (N) monocyte-derived immune cells and (O) neutrophils according to the mean fluorescence intensities by CLSM analysis. Data are expressed as means ± SEM (n = 3; ∗P < 0.05, ∗∗P < 0.01, and ∗∗∗P < 0.001).
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