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Article: Engineering nanoparticles to overcome barriers to immunotherapy.

Toy, Randall / Roy, Krishnendu

Bioengineering & translational medicine

2016 Volume 1, Issue 1, Page(s) 47–62

Abstract: Advances in immunotherapy have led to the development of a variety of promising therapeutics, including small molecules, proteins and peptides, monoclonal antibodies, and cellular therapies. Despite this wealth of new therapeutics, the efficacy of ... ...

Abstract	Advances in immunotherapy have led to the development of a variety of promising therapeutics, including small molecules, proteins and peptides, monoclonal antibodies, and cellular therapies. Despite this wealth of new therapeutics, the efficacy of immunotherapy has been limited by challenges in targeted delivery and controlled release, that is, spatial and temporal control on delivery. Particulate carriers, especially nanoparticles have been widely studied in drug delivery and vaccine research and are being increasingly investigated as vehicles to deliver immunotherapies. Nanoparticle-mediated drug delivery could provide several benefits, including control of biodistribution and transport kinetics, the potential for site-specific targeting, immunogenicity, tracking capability using medical imaging, and multitherapeutic loading. There are also a unique set of challenges, which include nonspecific uptake by phagocytic cells, off-target biodistribution, permeation through tissue (transport limitation), nonspecific immune-activation, and poor control over intracellular localization. This review highlights the importance of understanding the relationship between a nanoparticle's size, shape, charge, ligand density and elasticity to its vascular transport, biodistribution, cellular internalization, and immunogenicity. For the design of an effective immunotherapy, we highlight the importance of selecting a nanoparticle's physical characteristics (e.g., size, shape, elasticity) and its surface functionalization (e.g., chemical or polymer modifications, targeting or tissue-penetrating peptides) with consideration of its reactivity to the targeted microenvironment (e.g., targeted cell types, use of stimuli-sensitive biomaterials, immunogenicity). Applications of this rational nanoparticle design process in vaccine development and cancer immunotherapy are discussed.
Language	English
Publishing date	2016-06-20
Publishing country	United States
Document type	Journal Article ; Review
ISSN	2380-6761
ISSN	2380-6761
DOI	10.1002/btm2.10005
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: p38MAPK guards the integrity of endosomal compartments through regulating necrotic death.

Yao, Jia / Atasheva, Svetlana / Toy, Randall / Blanchard, Emmeline L / Santangelo, Philip J / Roy, Krishnendu / Mocarski, Edward S / Shayakhmetov, Dmitry M

Scientific reports

2022 Volume 12, Issue 1, Page(s) 16357

Abstract: Pathogens trigger activation of sensors of the innate immune system that initiate molecular signaling enabling appropriate host defense programs. Although recognition of pathogen-specific moieties or PAMPs by specialized receptors of the immune system is ...

Abstract	Pathogens trigger activation of sensors of the innate immune system that initiate molecular signaling enabling appropriate host defense programs. Although recognition of pathogen-specific moieties or PAMPs by specialized receptors of the immune system is well defined for a great number of pathogens, the mechanisms of sensing of pathogen-induced functional perturbations to the host cell remain poorly understood. Here we show that the disruption of endosomal compartments in macrophages by a bacterium or fully synthetic nanoparticles activates stress-response p38MAPK kinase, which triggers execution of cell death of a necrotic type. p38MAPK-mediated necrosis occurs in cells with a compound homozygous deletion of pyroptosis-inducing caspases-1 and -11, apoptotic caspase-8, and necroptosis-inducing receptor-interacting protein kinase-3 (RIPK3), indicating that all of these principal cell death mediators are dispensable for p38MAPK-induced necrosis in response to endosome rupture. p38MAPK-mediated necrosis is suppressed by the receptor-interacting protein kinase 1, RIPK1, and degradation of RIPK1 sensitizes macrophages to necrotic death. Since pathogen-induced cell death of necrotic types is implicated in host defense against infection, our results indicate that functional perturbations in host cells are sensed as a component of the innate immune system.
MeSH term(s)	Caspase 8 ; Endosomes ; Homozygote ; Humans ; Necrosis ; Pathogen-Associated Molecular Pattern Molecules ; Sequence Deletion ; p38 Mitogen-Activated Protein Kinases
Chemical Substances	Pathogen-Associated Molecular Pattern Molecules ; p38 Mitogen-Activated Protein Kinases (EC 2.7.11.24) ; Caspase 8 (EC 3.4.22.-)
Language	English
Publishing date	2022-09-29
Publishing country	England
Document type	Journal Article ; Research Support, U.S. Gov't, Non-P.H.S. ; Research Support, N.I.H., Extramural
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-022-20786-4
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Article ; Online: Enhanced immune responses to vaccine antigens in the corneal stroma.

Xia, Dengning / Toy, Randall / Pradhan, Pallab / Hejri, Amir / Chae, Jeremy / Grossniklaus, Hans E / Cursiefen, Claus / Roy, Krishnendu / Prausnitz, Mark R

Journal of controlled release : official journal of the Controlled Release Society

2022 Volume 353, Page(s) 434–446

Abstract: To examine the widely accepted dogma that the eye is an immune-privileged organ that can suppress antigen immunogenicity, we explored systemic immune responses to a model vaccine antigen (tetanus toxoid) delivered to six compartments of the rodent eye ( ... ...

Abstract	To examine the widely accepted dogma that the eye is an immune-privileged organ that can suppress antigen immunogenicity, we explored systemic immune responses to a model vaccine antigen (tetanus toxoid) delivered to six compartments of the rodent eye (ocular surface, corneal stroma, anterior chamber, subconjunctival space, suprachoroidal space, vitreous body). We discovered that antigens delivered to corneal stroma induced enhanced, rather than suppressed, antigen-specific immune responses, which were 18- to 30-fold greater than conventional intramuscular injection and comparable to intramuscular vaccination with alum adjuvant. Systemic immune responses to antigen delivered to the other ocular compartments were much weaker. The enhanced systemic immune responses after intrastromal injection were related to a sequence of events involving the formation of an antigen "depot" in the avascular stroma, infiltration of antigen-presenting cells, up-regulation of MHC class II and costimulatory molecules CD80/CD86, and induction of lymphangiogenesis in the corneal stroma facilitating sustained presentation of antigen to the lymphatic system. These enhanced immune responses in corneal stroma suggest new approaches to medical interventions for ocular immune diseases and vaccination methods.
MeSH term(s)	Corneal Stroma ; Antigen-Presenting Cells ; Immunity ; Antigens ; Vaccines
Chemical Substances	Antigens ; Vaccines
Language	English
Publishing date	2022-12-07
Publishing country	Netherlands
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ZDB-ID	632533-6
ISSN	1873-4995 ; 0168-3659
ISSN (online)	1873-4995
ISSN	0168-3659
DOI	10.1016/j.jconrel.2022.11.045
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Article ; Online: Polymeric Pathogen-Like Particles-Based Combination Adjuvants Elicit Potent Mucosal T Cell Immunity to Influenza A Virus.

Kingstad-Bakke, Brock / Toy, Randall / Lee, Woojong / Pradhan, Pallab / Vogel, Gabriela / Marinaik, Chandranaik B / Larsen, Autumn / Gates, Daisy / Luu, Tracy / Pandey, Bhawana / Kawaoka, Yoshihoro / Roy, Krishnendu / Suresh, M

Frontiers in immunology

2021 Volume 11, Page(s) 559382

Abstract: Eliciting durable and protective T cell-mediated immunity in the respiratory mucosa remains a significant challenge. Polylactic-co-glycolic acid (PLGA)-based cationic pathogen-like particles (PLPs) loaded with TLR agonists mimic biophysical properties of ...

Abstract	Eliciting durable and protective T cell-mediated immunity in the respiratory mucosa remains a significant challenge. Polylactic-co-glycolic acid (PLGA)-based cationic pathogen-like particles (PLPs) loaded with TLR agonists mimic biophysical properties of microbes and hence, simulate pathogen-pattern recognition receptor interactions to safely and effectively stimulate innate immune responses. We generated micro particle PLPs loaded with TLR4 (glucopyranosyl lipid adjuvant, GLA) or TLR9 (CpG) agonists, and formulated them with and without a mucosal delivery enhancing carbomer-based nanoemulsion adjuvant (ADJ). These adjuvants delivered intranasally to mice elicited high numbers of influenza nucleoprotein (NP)-specific CD8+ and CD4+ effector and tissue-resident memory T cells (T
MeSH term(s)	Adjuvants, Immunologic/pharmacology ; Animals ; Cell Line ; Dogs ; Immunity, Cellular/immunology ; Immunity, Innate/immunology ; Immunologic Memory/immunology ; Influenza A virus/immunology ; Intraepithelial Lymphocytes/immunology ; Lung/immunology ; Lung/virology ; Madin Darby Canine Kidney Cells ; Mice ; Mice, Inbred C57BL ; Orthomyxoviridae Infections/immunology ; Polylactic Acid-Polyglycolic Acid Copolymer/immunology ; Toll-Like Receptor 4/immunology
Chemical Substances	Adjuvants, Immunologic ; Toll-Like Receptor 4 ; Polylactic Acid-Polyglycolic Acid Copolymer (1SIA8062RS)
Language	English
Publishing date	2021-03-04
Publishing country	Switzerland
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2606827-8
ISSN	1664-3224 ; 1664-3224
ISSN (online)	1664-3224
ISSN	1664-3224
DOI	10.3389/fimmu.2020.559382
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Article: TLR7 and RIG-I dual-adjuvant loaded nanoparticles drive broadened and synergistic responses in dendritic cells in vitro and generate unique cellular immune responses in influenza vaccination

Toy, Randall / Keenum, M. Cole / Pradhan, Pallab / Phang, Katelynn / Chen, Patrick / Chukwu, Chinwendu / Nguyen, Lily Anh H / Liu, Jiaying / Jain, Sambhav / Kozlowski, Gabrielle / Hosten, Justin / Suthar, Mehul S / Roy, Krishnendu

Journal of controlled release. 2021 Feb. 10, v. 330

2021

Abstract: Although the existing flu vaccines elicit strong antigen-specific antibody responses, they fail to provide effective, long term protection – partly due to the absence of robust cellular memory immunity. We hypothesized that co-administration of ... ...

Abstract	Although the existing flu vaccines elicit strong antigen-specific antibody responses, they fail to provide effective, long term protection – partly due to the absence of robust cellular memory immunity. We hypothesized that co-administration of combination adjuvants, mirroring the flu-virus related innate signaling pathways, could elicit strong cellular immunity. Here, we show that the small molecule adjuvant R848 and the RNA adjuvant PUUC, targeting endosomal TLR7s and cytoplasmic RLRs respectively, when delivered together in polymer nanoparticles (NP), elicits a broadened immune responses in mouse bone marrow-derived dendritic cells (mBMDCs) and a synergistic response in both mouse and human plasmacytoid dendritic cells (pDCs). In mBMDCs, NP-R848-PUUC induced both NF-κB and interferon signaling. Interferon responses to co-delivered R848 and PUUC were additive in human peripheral blood mononuclear cells (PBMCs) and synergistic in human FLT3-differentiated mBMDCs and CAL-1 pDCs. Vaccination with NPs loaded with H1N1 Flu antigen, R848, and PUUC increased percentage of CD8+ T-cells in the lungs, percentage of antigen-specific CD4-T-cells in the spleen, and enhanced overall cytokine-secreting T cell percentages upon antigen restimulation. Also, in the spleen, T lymphopenia, especially after in vitro restimulation with dual adjuvants, was observed, indicating highly antigen-reactive T cells. Our results demonstrate that simultaneous engagement of TLR7 and RIG-I pathways using particulate carriers is a potential approach to improve cellular immunity in flu vaccination.
Keywords	CD4-positive T-lymphocytes ; CD8-positive T-lymphocytes ; Orthomyxoviridae ; RNA ; Toll-like receptor 7 ; adjuvants ; antigen-antibody reactions ; antigens ; cell-mediated immunity ; dendritic cells ; humans ; influenza ; influenza vaccination ; influenza vaccines ; interferons ; lungs ; mice ; nanoparticles ; polymers ; signal transduction ; spleen ; transcription factor NF-kappa B
Language	English
Dates of publication	2021-0210
Size	p. 866-877.
Publishing place	Elsevier B.V.
Document type	Article
ZDB-ID	632533-6
ISSN	1873-4995 ; 0168-3659
ISSN (online)	1873-4995
ISSN	0168-3659
DOI	10.1016/j.jconrel.2020.10.060
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Article ; Online: TLR7 and RIG-I dual-adjuvant loaded nanoparticles drive broadened and synergistic responses in dendritic cells in vitro and generate unique cellular immune responses in influenza vaccination.

Toy, Randall / Keenum, M Cole / Pradhan, Pallab / Phang, Katelynn / Chen, Patrick / Chukwu, Chinwendu / Nguyen, Lily Anh H / Liu, Jiaying / Jain, Sambhav / Kozlowski, Gabrielle / Hosten, Justin / Suthar, Mehul S / Roy, Krishnendu

Journal of controlled release : official journal of the Controlled Release Society

2020 Volume 330, Page(s) 866–877

Abstract: Although the existing flu vaccines elicit strong antigen-specific antibody responses, they fail to provide effective, long term protection - partly due to the absence of robust cellular memory immunity. We hypothesized that co-administration of ... ...

Abstract	Although the existing flu vaccines elicit strong antigen-specific antibody responses, they fail to provide effective, long term protection - partly due to the absence of robust cellular memory immunity. We hypothesized that co-administration of combination adjuvants, mirroring the flu-virus related innate signaling pathways, could elicit strong cellular immunity. Here, we show that the small molecule adjuvant R848 and the RNA adjuvant PUUC, targeting endosomal TLR7s and cytoplasmic RLRs respectively, when delivered together in polymer nanoparticles (NP), elicits a broadened immune responses in mouse bone marrow-derived dendritic cells (mBMDCs) and a synergistic response in both mouse and human plasmacytoid dendritic cells (pDCs). In mBMDCs, NP-R848-PUUC induced both NF-κB and interferon signaling. Interferon responses to co-delivered R848 and PUUC were additive in human peripheral blood mononuclear cells (PBMCs) and synergistic in human FLT3-differentiated mBMDCs and CAL-1 pDCs. Vaccination with NPs loaded with H1N1 Flu antigen, R848, and PUUC increased percentage of CD8+ T-cells in the lungs, percentage of antigen-specific CD4-T-cells in the spleen, and enhanced overall cytokine-secreting T cell percentages upon antigen restimulation. Also, in the spleen, T lymphopenia, especially after in vitro restimulation with dual adjuvants, was observed, indicating highly antigen-reactive T cells. Our results demonstrate that simultaneous engagement of TLR7 and RIG-I pathways using particulate carriers is a potential approach to improve cellular immunity in flu vaccination.
MeSH term(s)	Adjuvants, Immunologic ; Animals ; Dendritic Cells ; Humans ; Immunity, Cellular ; Influenza A Virus, H1N1 Subtype ; Influenza Vaccines ; Influenza, Human/prevention & control ; Leukocytes, Mononuclear ; Mice ; Nanoparticles ; Toll-Like Receptor 7 ; Vaccination
Chemical Substances	Adjuvants, Immunologic ; Influenza Vaccines ; Toll-Like Receptor 7
Language	English
Publishing date	2020-11-05
Publishing country	Netherlands
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	632533-6
ISSN	1873-4995 ; 0168-3659
ISSN (online)	1873-4995
ISSN	0168-3659
DOI	10.1016/j.jconrel.2020.10.060
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Article ; Online: Shaping cancer nanomedicine: the effect of particle shape on the in vivo journey of nanoparticles.

Toy, Randall / Peiris, Pubudu M / Ghaghada, Ketan B / Karathanasis, Efstathios

Nanomedicine (London, England)

2013 Volume 9, Issue 1, Page(s) 121–134

Abstract: Recent advances in nanoparticle technology have enabled the fabrication of nanoparticle classes with unique sizes, shapes and materials, which in turn has facilitated major advancements in the field of nanomedicine. More specifically, in the last decade, ...

Abstract	Recent advances in nanoparticle technology have enabled the fabrication of nanoparticle classes with unique sizes, shapes and materials, which in turn has facilitated major advancements in the field of nanomedicine. More specifically, in the last decade, nanoscientists have recognized that nanomedicine exhibits a highly engineerable nature that makes it a mainstream scientific discipline that is governed by its own distinctive principles in terms of interactions with cells and intravascular, transvascular and interstitial transport. This review focuses on the recent developments and understanding of the relationship between the shape of a nanoparticle and its navigation through different biological processes. It also seeks to illustrate that the shape of a nanoparticle can govern its in vivo journey and destination, dictating its biodistribution, intravascular and transvascular transport, and, ultimately, targeting of difficult to reach cancer sites.
MeSH term(s)	Humans ; Nanomedicine ; Nanoparticles/chemistry ; Nanoparticles/therapeutic use ; Neoplasms/therapy ; Tissue Distribution
Language	English
Publishing date	2013-12-19
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2277839-1
ISSN	1748-6963 ; 1743-5889
ISSN (online)	1748-6963
ISSN	1743-5889
DOI	10.2217/nnm.13.191
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Article ; Online: Modification of primary amines to higher order amines reduces in vivo hematological and immunotoxicity of cationic nanocarriers through TLR4 and complement pathways.

Toy, Randall / Pradhan, Pallab / Ramesh, Vijayeetha / Di Paolo, Nelson C / Lash, Blake / Liu, Jiaying / Blanchard, Emmeline L / Pinelli, Christopher J / Santangelo, Philip J / Shayakhmetov, Dmitry M / Roy, Krishnendu

Biomaterials

2019 Volume 225, Page(s) 119512

Abstract: For decades, cationic polymer nanoparticles have been investigated for nucleic acid delivery. Despite promising in vitro transfection results, most formulations have failed to translate into the clinic due to significant in vivo toxicity - especially ... ...

Abstract	For decades, cationic polymer nanoparticles have been investigated for nucleic acid delivery. Despite promising in vitro transfection results, most formulations have failed to translate into the clinic due to significant in vivo toxicity - especially when delivered intravenously. To address this significant problem, we investigated the detailed mechanisms that govern the complex in vivo systemic toxicity response to common polymeric nanoparticles. We determined that the toxicity response is material dependent. For branched polyethylenimine (bPEI) nanoparticles - toxicity is a function of multiple pathophysiological responses - triggering of innate immune sensors, induction of hepatic toxicity, and significant alteration of hematological properties. In contrast, for chitosan-based nanoparticles - systemic toxicity is primarily driven through innate immune activation. We further identified that modification of primary amines to secondary and tertiary amines using the small molecule imidazole-acetic-acid (IAA) ameliorates in vivo toxicity from both nanocarriers by different, material-specific mechanisms related to Toll-like receptor 4 activation (for bPEI) and complement activation driven neutrophil infiltration (for chitosan), respectively. Our results provide a detailed roadmap for evaluating in vivo toxicity of nanocarriers and identifies potential opportunities to reduce toxicity for eventual clinical translation.
MeSH term(s)	Acetic Acid/chemistry ; Amines/chemistry ; Animals ; Cations ; Chitosan/chemistry ; Chitosan/toxicity ; Complement System Proteins/metabolism ; Female ; Imidazoles/chemistry ; Mice ; Mice, Inbred C57BL ; Nanoparticles/toxicity ; Polyethyleneimine/chemistry ; Polyethyleneimine/toxicity ; Protein Corona/metabolism ; RAW 264.7 Cells ; RNA, Messenger/genetics ; RNA, Messenger/metabolism ; RNA, Small Interfering/metabolism ; Toll-Like Receptor 4/metabolism
Chemical Substances	Amines ; Cations ; Imidazoles ; Protein Corona ; RNA, Messenger ; RNA, Small Interfering ; Toll-Like Receptor 4 ; Polyethyleneimine (9002-98-6) ; Complement System Proteins (9007-36-7) ; Chitosan (9012-76-4) ; Acetic Acid (Q40Q9N063P)
Language	English
Publishing date	2019-09-21
Publishing country	Netherlands
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	603079-8
ISSN	1878-5905 ; 0142-9612
ISSN (online)	1878-5905
ISSN	0142-9612
DOI	10.1016/j.biomaterials.2019.119512
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Article ; Online: Targeted nanotechnology for cancer imaging.

Toy, Randall / Bauer, Lisa / Hoimes, Christopher / Ghaghada, Ketan B / Karathanasis, Efstathios

Advanced drug delivery reviews

2014 Volume 76, Page(s) 79–97

Abstract: Targeted nanoparticle imaging agents provide many benefits and new opportunities to facilitate accurate diagnosis of cancer and significantly impact patient outcome. Due to the highly engineerable nature of nanotechnology, targeted nanoparticles exhibit ... ...

Abstract	Targeted nanoparticle imaging agents provide many benefits and new opportunities to facilitate accurate diagnosis of cancer and significantly impact patient outcome. Due to the highly engineerable nature of nanotechnology, targeted nanoparticles exhibit significant advantages including increased contrast sensitivity, binding avidity and targeting specificity. Considering the various nanoparticle designs and their adjustable ability to target a specific site and generate detectable signals, nanoparticles can be optimally designed in terms of biophysical interactions (i.e., intravascular and interstitial transport) and biochemical interactions (i.e., targeting avidity towards cancer-related biomarkers) for site-specific detection of very distinct microenvironments. This review seeks to illustrate that the design of a nanoparticle dictates its in vivo journey and targeting of hard-to-reach cancer sites, facilitating early and accurate diagnosis and interrogation of the most aggressive forms of cancer. We will report various targeted nanoparticles for cancer imaging using X-ray computed tomography, ultrasound, magnetic resonance imaging, nuclear imaging and optical imaging. Finally, to realize the full potential of targeted nanotechnology for cancer imaging, we will describe the challenges and opportunities for the clinical translation and widespread adaptation of targeted nanoparticles imaging agents.
MeSH term(s)	Animals ; Contrast Media ; Diagnostic Imaging/methods ; Humans ; Nanoparticles ; Nanotechnology/methods ; Neoplasms/diagnosis
Chemical Substances	Contrast Media
Language	English
Publishing date	2014-08-09
Publishing country	Netherlands
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Review
ZDB-ID	639113-8
ISSN	1872-8294 ; 0169-409X
ISSN (online)	1872-8294
ISSN	0169-409X
DOI	10.1016/j.addr.2014.08.002
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Article: Modification of primary amines to higher order amines reduces in vivo hematological and immunotoxicity of cationic nanocarriers through TLR4 and complement pathways

Toy, Randall / Blanchard, Emmeline L / Di Paolo, Nelson C / Lash, Blake / Liu, Jiaying / Pinelli, Christopher J / Pradhan, Pallab / Ramesh, Vijayeetha / Roy, Krishnendu / Santangelo, Philip J / Shayakhmetov, Dmitry M

Biomaterials. 2019 Sept. 20,

2019

Abstract	For decades, cationic polymer nanoparticles have been investigated for nucleic acid delivery. Despite promising in vitro transfection results, most formulations have failed to translate into the clinic due to significant in vivo toxicity – especially when delivered intravenously. To address this significant problem, we investigated the detailed mechanisms that govern the complex in vivo systemic toxicity response to common polymeric nanoparticles. We determined that the toxicity response is material dependent. For branched polyethylenimine (bPEI) nanoparticles – toxicity is a function of multiple pathophysiological responses - triggering of innate immune sensors, induction of hepatic toxicity, and significant alteration of hematological properties. In contrast, for chitosan-based nanoparticles – systemic toxicity is primarily driven through innate immune activation. We further identified that modification of primary amines to secondary and tertiary amines using the small molecule imidazole-acetic-acid (IAA) ameliorates in vivo toxicity from both nanocarriers by different, material-specific mechanisms related to Toll-like receptor 4 activation (for bPEI) and complement activation driven neutrophil infiltration (for chitosan), respectively. Our results provide a detailed roadmap for evaluating in vivo toxicity of nanocarriers and identifies potential opportunities to reduce toxicity for eventual clinical translation.
Keywords	chitosan ; complement ; immunotoxicity ; intravenous injection ; nanocarriers ; nanoparticles ; neutrophils ; nucleic acids ; polyethyleneimine ; primary amines ; tertiary amines ; Toll-like receptor 4 ; transfection
Language	English
Dates of publication	2019-0920
Publishing place	Elsevier Ltd
Document type	Article
Note	Pre-press version
ZDB-ID	603079-8
ISSN	0142-9612
ISSN	0142-9612
DOI	10.1016/j.biomaterials.2019.119512
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