Oral nanomedicine for modulating immunity, intestinal barrier functions, and gut microbiome

Abstract

The gastrointestinal tract (GIT) affects not only local diseases in the GIT but also various systemic diseases. Factors that can affect the health and disease of both GIT and the human body include 1) the mucosal immune system composed of the gut-associated lymphoid tissues and the lamina propria, 2) the intestinal barrier composed of mucus and intestinal epithelium, and 3) the gut microbiota. Selective delivery of drugs, including antigens, immune-modulators, intestinal barrier enhancers, and gut-microbiome manipulators, has shown promising results for oral vaccines, immune tolerance, treatment of inflammatory bowel diseases, and other systemic diseases, including cancer. However, physicochemical and biological barriers of the GIT present significant challenges for successful translation. With the advances of novel nanomaterials, oral nanomedicine has emerged as an attractive option to not only overcome these barriers but also to selectively deliver drugs to the target sites in GIT. In this review, we discuss the GIT factors and physicochemical and biological barriers in the GIT. Furthermore, we present the recent progress of oral nanomedicine for oral vaccines, immune tolerance, and anti-inflammation therapies. We also discuss recent advances in oral nanomedicine designed to fortify the intestinal barrier functions and modulate the gut microbiota and microbial metabolites. Finally, we opine about the future directions of oral nano-immunotherapy.

Keywords: Gut microbiota; Intestinal barrier; Lamina propria; Mucosal Immunity; Nanomedicine; Oral immunotherapy; Peyer’s patches.

Figure 1.. Biomedical applications of oral nano-immunotherapy.

Oral nano-immunotherapy serves as the therapeutic platform for 1) oral vaccines, 2) immune tolerance, 3) treatment of inflammatory bowel diseases, 4) enhancing the intestinal barrier, and 5) modulating the gut microbiota.

Figure 2.. Immune system in the gastrointestinal tract.

(I) Specialized M cells in the epithelium overlying GALT mediates transcellular transport of antigens to DCs. (II) B-cells are activated to immunoglobulin-secreting cells that (III) migrate to the lamina propria and systemic mucosal effector sites and differentiate into IgA-secreting plasma cells. (IV) Antigen-carrying DCs migrate to mLNs to activate B-cells and T-cells, which (V) migrate to distant effector sites through the lymphatic system. (VI) Antigens can be recognized by DCs through diffusion through epithelial tight junctions, transfer across epithelial cells by transcellular routes, exosome-mediated delivery, or capturing from CX3CR1 high macrophages. (VII) Oral tolerance is initiated by antigen-carrying CD103+ DCs that induce Tregs, leading to (VIII) their dissemination to distant effector sites. (IX) Antigens also reach to the liver and peripheral lymph nodes. (X) Oral immunotherapy could trigger protective immunity or tolerogenic immunity, depending on the target cells and local signals. Created by BioRender.com.

Figure 3.. Maintenance of the intestinal barrier functions.

The intestinal barrier is composed of intestinal epithelium and mucosal layer. Epithelial cells are connected by a series of intercellular tight junctions, which are responsible for the intestinal barrier functions. The mucosal and gut microbiota layers protect the body from pathogens. Disrupted of intestinal barrier is associated with various diseases, including IBD, hyperglycemia, infection, and cancer. Created by BioRender.com.

Figure 4.. The role of the gut microbiota in various diseases.

Dysbiotic gut microbiota is associated with various local and systemic diseases, including infection, inflammation-associated diseases, and cancer. Created by BioRender.com.

Figure 5.. Oral nanomedicine for targeting the lamina propria.

Schematic illustration of TPP(sodium triphosphate)-PPM(a mannosylated bioreducible cationic polymer)/siRNA NP (NP) formation and macrophage-targeting delivery, and the release of siRNAs to the cytoplasm. Reproduced with permission from [162].

Figure 6.. Oral nanomedicine for improving the intestinal barrier functions.

a, Self-assembly procedure of single-chain CD98 antibody-functionalized siRNA-loaded NPs. b, Specificity of scCD98-functionalized FITC-siRNA–loaded NPs (green) against in vitro colonic epithelial cells (Colon-26 cells; top), macrophages (RAW 267.4; bottom). c-d, In vivo therapeutic efficacy of siCD98 NPs as measured by body weight changes (c), CD98 mRNA levels (d; left), and TNF-alpha mRNA levels (d; right) in the colon of DSS-induced colitis mice. Reproduced with permission from [204].

Figure 7.. Oral nanomedicine for modulating the gut microbiome for anti-cancer therapy.

a, Dextran-encapsulated probiotics (C. butyricum) (Spores-dex) regulate gut microbiota and suppress colon cancer. b, Short-chain fatty acids, one of the microbial metabolites, regulate gut microbiota and suppress tumor growth. c-e, In vivo therapeutic efficacy of diclofenac-loaded spores-dex (DC@spores-dex) in mice bearing subcutaneous (c, d) or orthotopic CT26 tumors (c, e). Reproduced with permission from [217].

Figure 8.. Oral nanomedicine for altering the gut microbiome for IBD therapy.

a, Schematic of hyaluronic acid-bilirubin NPs (HABN) self-assembled from hyaluronic acid-bilirubin conjugate (HA–BR) and their TEM images. HABN accumulates in inflamed colon and exerts therapeutic effects against acute colitis by targeted modulation of immune systems, intestinal barrier, and gut microbiota. b, Orally administered HABN modulates the gut microbiome in DSS-colitis mice. Heatmap of the relative abundance of family-level taxa (rows) in each mouse (columns). c, In vivo therapeutic efficacy of HABN in DSS-colitis mice. Antibiotics partially reduced the efficacy of HABN, showing the importance of HABN-mediated modulation of the gut microbiota. Reproduced with permission from [234].

Figure 9.. Oral nanomedicine for vaccine applications.

a, TEM images of non-lectinized liposomes and lectinized liposomes. b, In vivo M cell-targeting ability of lectinized liposomes (shown by arrows) c-e, In vivo protective immunity induced by orally administered liposomes carrying hepatitis B surface antigen as measured by serum antibody levels (c), sIgA levels in mucosal secretion (d), and cytokine (IL-2 and IFN-γ) levels in mouse spleen homogenates (e). f-g, In vivo enhancement of TLR2-mediated transepithelial transport of orally administered proteosomes, as measured by counting the number of microspheres in FAE (f) and immunofluorescence images with microspheres (green) associated with M cells (red; g) and intraepithelial CD11c+ DCs (red; h) in the FAE of Peyer's patch. Panels a-e and f-g are reproduced with permission from [250] and [254], respectively.

Figure 10.. Oral nanomedicine for inducing immune tolerance.

a, SEM images of (A) NP/pep (type II collagen peptide), (B) NP/PEG-pep1 (mPEG-SPDP-peptide), and (C) NP/PEG-pep2 (mPEG-OD-peptide). b-c, In vivo IL-4 (b) and IL-10 (c)-producing T-cell induction activity of NP/PEG-pep1 or NP/PEG-pep2 in the Peyer's patches of DBA/1 mice, as analyzed by FACS. d, In vivo biodistribution of orally administered FVIII DNA-chitosan NPs as measured by quantitative PCR g-h, In vivo functional FVIII protein production (g) and phenotypic correction (h) activities of orally administered FVIII DNA-chitosan NPs, measured by a tail-clip assay. i, In vivo tolerance induction activity against functional FVIII protein of orally administered FVIII DNA-chitosan NPs in hemophilia A mice, as measured by ELISA-mediated detection of plasma FVIIII antibody levels. Panels a-d, e-h, and i are reproduced with permission from [269], [268], and [177], respectively.