In situ T-cell transfection by anti-CD3-conjugated lipid nanoparticles leads to T-cell activation, migration, and phenotypic shift

Kheirolomoom, Azadeh; Kare, Aris J; Ingham, Elizabeth S.; Paulmurugan, Ramasamy; Robinson, Elise; Baikoghli, Mo; Inayathullah, Mohammed; Seo, Jai Woong; Wang, James; Fite, Brett Z.; Wu, Bo; Tumbale, Spencer K.; Raie, Marina; Cheng, R. Holland; Nichols, Lisa A.; Borowsky, Alexander D.; Ferrara, Katherine W.

doi:10.1016/j.biomaterials.2021.121339

Cited by 48 publications

(42 citation statements)

References 56 publications

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“…Elevation in glycolysis is related to an increase in glucose transporter proteins, including GLUT1, which is highly overexpressed in cancer cells [49] In addition, an increase in glycolysis is accompanied by a shunt of central carbon metabolites from the citric acid cycle, including increased expression of pyruvate dehydrogenase kinase 3 (PDK3), which promotes lactate production. A similar phenomenon is called the SAS-NPs moDCs M2 macrophages to M1 phenotype and restored the activity of CD8 + T cells [121] Silica NPs DCs Generating pro-inflammatory cytokines through the P2X7R [118,122] XL-MSNs macrophages Promoting M1 to M2 and inducing pyroptosis [134,135] HA-PEI NPs macrophages Modulating the polarity of macrophages [136,137] TiO2 anatase NPs Macrophages, neutrophils Inducing CD8 + T cell response initiation [140] TiO2, CeO2, and ZnO NPs neutrophil decreasing CD35 but increasing CD66b and CD63 expression [145] siVCAM-1 NPs neutrophil exerting an anti-inflammatory effect [144] SWCNTs neutrophil inhibiting both neutrophil migration and adhesion [146] Nanoparticle-bound NKT NKT activating T cell immune responses [149] USSN T cell receptors promoting T-cell activation, migration, and phenotypic transformation [150] lipid NPs T-cell anti-CD3-conjugated [151] liposomal PHA T-cell mediating T-cell activation [152] LNPs CD4 + cells mediating T-cell activation [155] Warburg effect in cancer cells [50]. Furthermore, pyruvate kinase M2 (PKM2) represents a unique link between aHSCs and cancer cells that promote aerobic glycolysis [51].…”

Section: Engineered Nps Regulated Metabolic Reprogramming-associated ...mentioning

confidence: 99%

“…APCs indirectly target T cells, whereas, NPs directly stimulate T lymphocytes, making it an ideal option.Ultrasmall silica NPs (USSN) (<10 nm in diameter) binds to T cell receptors and CD3 to induce the activation of T cell [150]. Situ T-cell transfection with anti-CD3-conjugated lipid NPs promotes T-cell activation, migration, and phenotypic transformation [151]. PEGylated liposomes, consisting of DPPC and cholesterol, can efficiently load PHA.…”

Section: Targeted T Cells An Acquired Immune-like Therapymentioning

confidence: 99%

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Remodeling the hepatic fibrotic microenvironment with emerging nanotherapeutics: a comprehensive review

et al. 2023

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Liver fibrosis could be the last hope for treating liver cancer and remodeling of the hepatic microenvironment has emerged as a strategy to promote the ablation of liver fibrosis. In recent years, especially with the rapid development of nanomedicine, hepatic microenvironment therapy has been widely researched in studies concerning liver cancer and fibrosis. In this comprehensive review, we summarized recent advances in nano therapy-based remodeling of the hepatic microenvironment. Firstly, we discussed novel strategies for regulatory immune suppression caused by capillarization of liver sinusoidal endothelial cells (LSECs) and macrophage polarization. Furthermore, metabolic reprogramming and extracellular matrix (ECM) deposition are caused by the activation of hepatic stellate cells (HSCs). In addition, recent advances in ROS, hypoxia, and impaired vascular remodeling in the hepatic fibrotic microenvironment due to ECM deposition have also been summarized. Finally, emerging nanotherapeutic approaches based on correlated signals were discussed in this review. We have proposed novel strategies such as engineered nanotherapeutics targeting antigen-presenting cells (APCs) or direct targeting T cells in liver fibrotic immunotherapy to be used in preventing liver fibrosis. In summary, this comprehensive review illustrated the opportunities in drug targeting and nanomedicine, and the current challenges to be addressed. Graphical Abstract

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Section: Engineered Nps Regulated Metabolic Reprogramming-associated ...mentioning

confidence: 99%

Section: Targeted T Cells An Acquired Immune-like Therapymentioning

confidence: 99%

Remodeling the hepatic fibrotic microenvironment with emerging nanotherapeutics: a comprehensive review

et al. 2023

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“…As a result, it is difficult to comment on the clinical significance of ∼3% to 5% mCherry + trophoblasts, endothelial cells, and immune cells in the placenta. However, we can make comparisons to other works that have delivered mRNA LNPs to extrahepatic organs, such as the spleen and lymph nodes, and characterized cellular level delivery. ,, Kheirolomoom et al developed a CD3-targeting LNP platform encapsulating mCherry mRNA and observed positivity rates in splenic immune cells ranging from ∼1.5% to 4% . Fenton et al utilized fluorescently labeled mRNA and demonstrated splenic immune cell association positivity rates ranging from ∼2% to 6% .…”

Section: Resultsmentioning

confidence: 99%

Ionizable Lipid Nanoparticles for In Vivo mRNA Delivery to the Placenta during Pregnancy

et al. 2023

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Ionizable lipid nanoparticles (LNPs) are the most clinically advanced nonviral platform for mRNA delivery. While they have been explored for applications including vaccines and gene editing, LNPs have not been investigated for placental insufficiency during pregnancy. Placental insufficiency is caused by inadequate blood flow in the placenta, which results in increased maternal blood pressure and restricted fetal growth. Therefore, improving vasodilation in the placenta can benefit both maternal and fetal health. Here, we engineered ionizable LNPs for mRNA delivery to the placenta with applications in mediating placental vasodilation. We designed a library of ionizable lipids to formulate LNPs for mRNA delivery to placental cells and identified a lead LNP that enables in vivo mRNA delivery to trophoblasts, endothelial cells, and immune cells in the placenta. Delivery of this top LNP formulation encapsulated with VEGF-A mRNA engendered placental vasodilation, demonstrating the potential of mRNA LNPs for protein replacement therapy during pregnancy to treat placental disorders.

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“…Rodents have often been used as a well-established model for studying generation of antibodies against both liposomes ,,, and LNPs , upon repeated exposure of such nanoparticles, and mice were therefore determined to be a suited model for validating the SPAM assay. To this end, we exposed mice to intravenous injections of generic LNPs (dosed at 300 ng/kg mRNA) based on the ionizable lipid DLin-MC3-DMAa formulation commonly used in literature for studies on mRNA delivery, − also being similar to the clinically approved LNP for delivery of the siRNA drug Onpattro . We chose such a generic LNP platform in order to not only reflect the ability of antibodies generated against Comirnaty to bind subsequent doses of the same vaccine, but also investigate how such antibodies could cross-react with other LNP types, as these may find widespread use for several therapeutic areas in the future.…”

Section: Resultsmentioning

confidence: 99%

Investigating Generation of Antibodies against the Lipid Nanoparticle Vector Following COVID-19 Vaccination with an mRNA Vaccine

et al. 2023

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Despite the success of mRNA-based vaccines against infectious diseases (including COVID-19), safety concerns have been raised relating to the lipid nanoparticles (LNPs) used to deliver the mRNA cargo. Antibodies against the polyethylene glycol (PEG) coating on these non-viral vectors are present in the general population and can in some instances induce allergic reactions. Furthermore, treatment with PEGylated therapeutics may increase the plasma concentration of such anti-PEG antibodies. The widespread use of PEGylated nanoparticles for mRNA vaccines concerns researchers and clinicians about a potential rise in future cases of allergic reactions against mRNA vaccines and cross-reactions with other PEGylated therapeutics. To determine if vaccination with Comirnaty increased the plasma concentration of antibodies against LNPs, we investigated the blood plasma concentration of anti-LNP antibodies in healthy individuals before and after vaccination with the mRNA-based COVID-19 vaccine Comirnaty (BNT162b2). Blood samples were acquired from 21 healthy adults before vaccination, 3–4 weeks after the first vaccination dose but before the second dose, and 2–6 months after the second (booster) dose. The blood plasma concentration of antibodies recognizing the LNPs was analyzed using a microscopy-based assay capable of measuring antibody-binding to individual authentic LNPs. No significant increase in anti-LNP antibodies was observed after two doses of Comirnaty. The LNPs used for intramuscular delivery of mRNA in the vaccine against COVID-19, Comirnaty, do, therefore, not seem to induce the generation of anti-vector antibodies.

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In situ T-cell transfection by anti-CD3-conjugated lipid nanoparticles leads to T-cell activation, migration, and phenotypic shift

Cited by 48 publications

References 56 publications

Remodeling the hepatic fibrotic microenvironment with emerging nanotherapeutics: a comprehensive review

Remodeling the hepatic fibrotic microenvironment with emerging nanotherapeutics: a comprehensive review

Ionizable Lipid Nanoparticles for In Vivo mRNA Delivery to the Placenta during Pregnancy

Investigating Generation of Antibodies against the Lipid Nanoparticle Vector Following COVID-19 Vaccination with an mRNA Vaccine

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