Mechanistic contributions of Kupffer cells and liver sinusoidal endothelial cells in nanoparticle-induced antigen-specific immune tolerance

Casey, Liam M.; Hughes, Kevin R.; Saunders, Michael N; Miller, Stephen D.; Pearson, Ryan M.; Shea, Lonnie D.

doi:10.1016/j.biomaterials.2022.121457

Cited by 22 publications

(13 citation statements)

References 58 publications

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“…We envision that altering the size and surface chemistry of the polyplexes may aid in achieving transfection in hepatic or other extrahepatic tissues as previously described . Importantly, our data support non-inflammatory mRNA delivery to the lungs using polyMDET and polyMDET-Cp polyplexes, which offers significant potential to develop tolerogenic mRNA vaccines for the treatment of autoimmunity or allergy based on several studies utilizing polymeric nanoparticles for induction of antigen (Ag)-specific immune tolerance. − Alternatively, the incorporation of nucleic acid adjuvants targeting toll-like receptor signaling or the cGas/STING pathway may provide the opportunity to develop targeted cancer vaccines. , …”

Section: Discussionsupporting

confidence: 53%

Excipient-Free Ionizable Polyester Nanoparticles for Lung-Selective and Innate Immune Cell Plasmid DNA and mRNA Transfection

Chakraborty

Dharmaraj

Truong

et al. 2022

ACS Appl. Mater. Interfaces

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Extrahepatic nucleic acid delivery using polymers typically requires the synthesis and purification of custom monomers, post-synthetic modifications, and incorporation of additional excipients to augment their stability, endosomal escape, and in vivo effectiveness. Here, we report the development of a single-component and excipient-free, polyester-based nucleic acid delivery nanoparticle platform comprising ionizable N-methyldiethanolamine (MDET) and various hydrophobic alkyl diols (Cp) that achieves lung-selective nucleic acid transfection in vivo. PolyMDET and polyMDET-Cp polyplexes displayed high serum and enzymatic stability, while delivering pDNA or mRNA to "hard-to-transfect" innate immune cells. PolyMDET-C4 and polyMDET-C6 mediated high protein expression in lung alveolar macrophages and dendritic cells without inducing tissue damage or systemic inflammatory responses. Improved strategies using readily available starting materials to produce a simple, excipient-free, non-viral nucleic acid delivery platform with lung-selective and innate immune cell tropism has the potential to expedite clinical deployment of polymer-based genetic medicines.

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Section: Discussionsupporting

confidence: 53%

Excipient-Free Ionizable Polyester Nanoparticles for Lung-Selective and Innate Immune Cell Plasmid DNA and mRNA Transfection

Chakraborty

Dharmaraj

Truong

et al. 2022

ACS Appl. Mater. Interfaces

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“…We previously developed polymer-based NPs as an in vivo drug delivery system, where encephalitogenic peptide Ags were conjugated to PLGA (P-Ag) and stoichiometrically incorporated into PLGA NPs to induce Ag-specific immune tolerance in a mouse model of multiple sclerosis . Notably, the biodistribution of the PLGA NPs was primarily found in the liver and spleen, where P-Ag could be processed and presented to autoreactive CD4 + T cells . We hypothesized that L-Ags along with P-Ags could be incorporated into PLGA NPs to combine advantages of both delivery platforms while overcoming their disadvantages.…”

Section: Resultsmentioning

confidence: 99%

“…24 Notably, the biodistribution of the PLGA NPs was primarily found in the liver and spleen, where P-Ag could be processed and presented to autoreactive CD4 + T cells. 40 We hypothesized that L-Ags along with P-Ags could be incorporated into PLGA NPs to combine advantages of both delivery platforms while overcoming their disadvantages. PLGA NPs can encapsulate hydrophobic polymer conjugates as well as protect encapsulated L-Ags or P-Ags from enzymatic degradation, combining multiple advantages of two drug delivery mechanisms: (i) depoting by lipids and (ii) endocytosis by NPs to achieve controlled delivery of Ags to B cells and DCs.…”

Section: ■ Resultsmentioning

confidence: 99%

Lipid–Polymer Hybrid Nanoparticles Utilize B Cells and Dendritic Cells to Elicit Distinct Antigen-Specific CD4⁺ and CD8⁺ T Cell Responses

Zhang

Scotland

Jiao

et al. 2023

ACS Appl. Bio Mater.

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Antigen-presenting cells (APCs) are widely studied for treating immunemediated diseases, and dendritic cells (DCs) are potent APCs that uptake and present antigens (Ags). However, DCs face several challenges that hinder their clinical translation due to their inability to control Ag dosing and low abundance in peripheral blood. B cells are a potential alternative to DCs, but their poor nonspecific Ag uptake capabilities compromise controllable priming of T cells. Here, we developed phospholipid-conjugated Ags (L-Ags) and lipid−polymer hybrid nanoparticles (L/P-Ag NPs) as delivery platforms to expand the range of accessible APCs for use in T cell priming. These delivery platforms were evaluated using DCs, CD40-activated B cells, and resting B cells to understand the impacts of various Ag delivery mechanisms for generation of Ag-specific T cell responses. L-Ag delivery (termed depoting) of MHC class I-and II-restricted Ags successfully loaded all APC types in a tunable manner and primed both Ag-specific CD8 + and CD4 + T cells, respectively. Incorporating L-Ags and polymer-conjugated Ags (P-Ag) into NPs can direct Ags to different uptake pathways to engineer the dynamics of presentation and shape T cell responses. DCs were capable of processing and presenting Ag delivered from both L-and P-Ag NPs, yet B cells could only utilize Ag delivered from L-Ag NPs, which led to differential cytokine secretion profiles in coculture studies. Altogether, we show that L-Ags and P-Ags can be rationally paired within a single NP to leverage distinct delivery mechanisms to access multiple Ag processing pathways in two APC types, offering a modular delivery platform for engineering Ag-specific immunotherapies.

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“…Meanwhile, KCs are capable to down-regulate own TLR4-signaling pathways under the long-term exposure to gut-derived LPS (low dose) partly due to the induction of interleukin-1 receptor-associated kinase M. This LPS tolerance may be necessary to maintain the homeostasis of the gut-liver axis ( Liu et al, 2008 ). A recent study also identified that KCs treated with polymeric nanoparticles which contain disease-relevant antigens are sufficient to mediate immune tolerance in experimental autoimmune encephalomyelitis (EAE) ( Casey et al, 2022 ). Figure 1 outlines the roles of hepatic macrophages in liver inflammation.…”

Section: Hepatic Macrophages In Liver Inflammationmentioning

confidence: 99%

Crosstalk between liver macrophages and gut microbiota: An important component of inflammation-associated liver diseases

Zhou

Pan

2022

Front. Cell Dev. Biol.

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Hepatic macrophages have been recognized as primary sensors and responders in liver inflammation. By processing host or exogenous biochemical signals, including microbial components and metabolites, through the gut-liver axis, hepatic macrophages can both trigger or regulate inflammatory responses. Crosstalk between hepatic macrophages and gut microbiota is an important component of liver inflammation and related liver diseases, such as acute liver injury (ALI), alcoholic liver disease (ALD), and nonalcoholic fatty liver disease (NAFLD). This review summarizes recent advances in knowledge related to the crosstalk between hepatic macrophages and gut microbiota, including the therapeutic potential of targeting hepatic macrophages as a component of gut microecology in inflammation-associated liver diseases.

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Mechanistic contributions of Kupffer cells and liver sinusoidal endothelial cells in nanoparticle-induced antigen-specific immune tolerance

Cited by 22 publications

References 58 publications

Excipient-Free Ionizable Polyester Nanoparticles for Lung-Selective and Innate Immune Cell Plasmid DNA and mRNA Transfection

Excipient-Free Ionizable Polyester Nanoparticles for Lung-Selective and Innate Immune Cell Plasmid DNA and mRNA Transfection

Lipid–Polymer Hybrid Nanoparticles Utilize B Cells and Dendritic Cells to Elicit Distinct Antigen-Specific CD4⁺ and CD8⁺ T Cell Responses

Crosstalk between liver macrophages and gut microbiota: An important component of inflammation-associated liver diseases

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Mechanistic contributions of Kupffer cells and liver sinusoidal endothelial cells in nanoparticle-induced antigen-specific immune tolerance

Cited by 22 publications

References 58 publications

Excipient-Free Ionizable Polyester Nanoparticles for Lung-Selective and Innate Immune Cell Plasmid DNA and mRNA Transfection

Excipient-Free Ionizable Polyester Nanoparticles for Lung-Selective and Innate Immune Cell Plasmid DNA and mRNA Transfection

Lipid–Polymer Hybrid Nanoparticles Utilize B Cells and Dendritic Cells to Elicit Distinct Antigen-Specific CD4+ and CD8+ T Cell Responses

Crosstalk between liver macrophages and gut microbiota: An important component of inflammation-associated liver diseases

Contact Info

Product

Resources

About

Lipid–Polymer Hybrid Nanoparticles Utilize B Cells and Dendritic Cells to Elicit Distinct Antigen-Specific CD4⁺ and CD8⁺ T Cell Responses