Special Issue "Immune Responses to Nanomaterials for Biomedical Applications"

A special issue of Nanomaterials (ISSN 2079-4991). This special issue belongs to the section "Biology and Medicines".

Deadline for manuscript submissions: 15 October 2020.

Special Issue Editor

Dr. Giuseppe Bardi
Website
Guest Editor

Special Issue Information

Dear Colleagues,

Nanotechnology has consolidated its success in the past years by producing novel devices and materials, which are currently applied in several fields of research and industry. Our interest is focused on biomedical applications of nanotechnologies to improve the therapeutics’ performances, as well as diagnostics. Successful nanodevices for drug or gene delivery, imaging or synthesized with materials acting per se (e.g., nanozimes) require full biocompatibility. Recent literature has highlighted the importance of host immune responses to nanomaterials as a critical issue to be addressed in order to create safe-by-design nanotools.

The present Special Issue would like to overcome the “classical nanotoxicology” as limited to toxicity results on cell death mechanisms, rather providing information on the several interactions that the immune system has with nanomaterials developed to biomedical applications. Novel results on immune cell, tissue or different animal models’ inflammatory responses to nanomaterials will be welcome, as well as critical review articles challenging the present knowledge and offering an expert platform to discussion.

Dr. Giuseppe Bardi
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All papers will be peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Nanomaterials is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2000 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • nanomaterials
  • biomedical applications
  • immune-compatibility
  • innate immune system
  • adaptive immune system
  • immune responses
  • inflammation
  • immune cells
  • immune response
  • inflammatory mediators
  • cytokines
  • chemokines
  • phagocytosis

Published Papers (8 papers)

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Research

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Open AccessArticle
Indocyanine Green-Nexturastat A-PLGA Nanoparticles Combine Photothermal and Epigenetic Therapy for Melanoma
Nanomaterials 2020, 10(1), 161; https://doi.org/10.3390/nano10010161 - 17 Jan 2020
Cited by 1
Abstract
In this study, we describe poly (lactic-co-glycolic) acid (PLGA)-based nanoparticles that combine photothermal therapy (PTT) with epigenetic therapy for melanoma. Specifically, we co-encapsulated indocyanine green (ICG), a PTT agent, and Nexturastat A (NextA), an epigenetic drug within PLGA nanoparticles (ICG-NextA-PLGA; INAPs). [...] Read more.
In this study, we describe poly (lactic-co-glycolic) acid (PLGA)-based nanoparticles that combine photothermal therapy (PTT) with epigenetic therapy for melanoma. Specifically, we co-encapsulated indocyanine green (ICG), a PTT agent, and Nexturastat A (NextA), an epigenetic drug within PLGA nanoparticles (ICG-NextA-PLGA; INAPs). We hypothesized that combining PTT with epigenetic therapy elicits favorable cytotoxic and immunomodulatory responses that result in improved survival in melanoma-bearing mice. We utilized a nanoemulsion synthesis scheme to co-encapsulate ICG and NextA within stable and monodispersed INAPs. The INAPs exhibited concentration-dependent and near-infrared (NIR) laser power-dependent photothermal heating characteristics, and functioned as effective single-use agents for PTT of melanoma cells in vitro. The INAPs functioned as effective epigenetic therapy agents by inhibiting the expression of pan-histone deacetylase (HDAC) and HDAC6-specific activity in melanoma cells in vitro. When used for both PTT and epigenetic therapy in vitro, the INAPs increased the expression of co-stimulatory molecules and major histocompatibility complex (MHC) Class I in melanoma cells relative to controls. These advantages persisted in vivo in a syngeneic murine model of melanoma, where the combination therapy slowed tumor progression and improved median survival. These findings demonstrate the potential of INAPs as agents of PTT and epigenetic therapy for melanoma. Full article
(This article belongs to the Special Issue Immune Responses to Nanomaterials for Biomedical Applications)
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Open AccessCommunication
Effects of Metal Oxide Nanoparticles on Toll-Like Receptor mRNAs in Human Monocytes
Nanomaterials 2020, 10(1), 127; https://doi.org/10.3390/nano10010127 - 10 Jan 2020
Abstract
For the widespread application of nanotechnology in biomedicine, it is necessary to obtain information about their safety. A critical problem is presented by the host immune responses to nanomaterials. It is assumed that the innate immune system plays a crucial role in the [...] Read more.
For the widespread application of nanotechnology in biomedicine, it is necessary to obtain information about their safety. A critical problem is presented by the host immune responses to nanomaterials. It is assumed that the innate immune system plays a crucial role in the interaction of nanomaterials with the host organism. However, there are only fragmented data on the activation of innate immune system factors, such as toll-like receptors (TLRs), by some nanoparticles (NPs). In this study, we investigated TLRs’ activation by clinically relevant and promising NPs, such as Fe3O4, TiO2, ZnO, CuO, Ag2O, and AlOOH. Cytotoxicity and effects on innate immunity factors were studied in THP-1(Tohoku Hospital Pediatrics-1) cell culture. NPs caused an increase of TLR-4 and -6 expression, which was comparable with the LPS-induced level. This suggests that the studied NPs can stimulate the innate immune system response inside the host. The data obtained should be taken into account in future research and to create safe-by-design biomedical nanomaterials. Full article
(This article belongs to the Special Issue Immune Responses to Nanomaterials for Biomedical Applications)
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Open AccessArticle
Prolonged Release and Functionality of Interleukin-10 Encapsulated within PLA-PEG Nanoparticles
Nanomaterials 2019, 9(8), 1074; https://doi.org/10.3390/nano9081074 - 26 Jul 2019
Cited by 3
Abstract
Inflammation, as induced by the presence of cytokines and chemokines, is an integral part of chlamydial infections. The anti-inflammatory cytokine, interleukin (IL)-10, has been reported to efficiently suppress the secretion of inflammatory cytokines triggered by Chlamydia in mouse macrophages. Though IL-10 is employed [...] Read more.
Inflammation, as induced by the presence of cytokines and chemokines, is an integral part of chlamydial infections. The anti-inflammatory cytokine, interleukin (IL)-10, has been reported to efficiently suppress the secretion of inflammatory cytokines triggered by Chlamydia in mouse macrophages. Though IL-10 is employed in clinical applications, its therapeutic usage is limited due to its short half-life. Here, we document the successful encapsulation of IL-10 within the biodegradable polymeric nanoparticles of PLA-PEG (Poly (lactic acid)-Poly (ethylene glycol), to prolong its half-life. Our results show the encapsulated-IL-10 size (~238 nm), zeta potential (−14.2 mV), polydispersity index (0.256), encapsulation efficiency (~77%), and a prolonged slow release pattern up to 60 days. Temperature stability of encapsulated-IL-10 was favorable, demonstrating a heat capacity of up to 89 °C as shown by differential scanning calorimetry analysis. Encapsulated-IL-10 modulated the release of IL-6 and IL-12p40 in stimulated macrophages in a time- and concentration-dependent fashion, and differentially induced SOCS1 and SOCS3 as induced by chlamydial stimulants in macrophages. Our finding offers the tremendous potential for encapsulated-IL-10 not only for chlamydial inflammatory diseases but also biomedical therapeutic applications. Full article
(This article belongs to the Special Issue Immune Responses to Nanomaterials for Biomedical Applications)
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Open AccessArticle
Prediction of Gold Nanoparticle and Microwave-Induced Hyperthermia Effects on Tumor Control via a Simulation Approach
Nanomaterials 2019, 9(2), 167; https://doi.org/10.3390/nano9020167 - 29 Jan 2019
Cited by 3
Abstract
Hyperthermia acts as a powerful adjuvant to radiation therapy and chemotherapy. Recent advances show that gold nanoparticles (Au-NPs) can mediate highly localized thermal effects upon interaction with laser radiation. The purpose of the present study was to investigate via in silico simulations the [...] Read more.
Hyperthermia acts as a powerful adjuvant to radiation therapy and chemotherapy. Recent advances show that gold nanoparticles (Au-NPs) can mediate highly localized thermal effects upon interaction with laser radiation. The purpose of the present study was to investigate via in silico simulations the mechanisms of Au-NPs and microwave-induced hyperthermia, in correlation to predictions of tumor control (biological endpoints: tumor shrinkage and cell death) after hyperthermia treatment. We also study in detail the dependence of the size, shape and structure of the gold nanoparticles on their absorption efficiency, and provide general guidelines on how one could modify the absorption spectrum of the nanoparticles in order to meet the needs of specific applications. We calculated the hyperthermia effect using two types of Au-NPs and two types of spherical tumors (prostate and melanoma) with a radius of 3 mm. The plasmon peak for the 30 nm Si-core Au-coated NPs and the 20 nm Au-NPs was found at 590 nm and 540 nm, respectively. Considering the plasmon peaks and the distribution of NPs in the tumor tissue, the induced thermal profile was estimated for different intervals of time. Predictions of hyperthermic cell death were performed by adopting a three-state mathematical model, where “three-state” includes (i) alive, (ii) vulnerable, and (iii) dead states of the cell, and it was coupled with a tumor growth model. Our proposed methodology and preliminary results could be considered as a proof-of-principle for the significance of simulating accurately the hyperthermia-based tumor control involving the immune system. We also propose a method for the optimization of treatment by overcoming thermoresistance by biological means and specifically through the targeting of the heat shock protein 90 (HSP90), which plays a critical role in the thermotolerance of cells and tissues. Full article
(This article belongs to the Special Issue Immune Responses to Nanomaterials for Biomedical Applications)
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Review

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Open AccessReview
Neutrophils as Main Players of Immune Response towards Nondegradable Nanoparticles
Nanomaterials 2020, 10(7), 1273; https://doi.org/10.3390/nano10071273 (registering DOI) - 29 Jun 2020
Abstract
Many nano/microparticles (n/µP), to which our body is exposed, have no physiological way of removal. Our immune system sense these “small particulate objects”, and tries to decrease their harmfulness. Since oxidation, phagocytosis and other methods of degradation do not work with small, chemically [...] Read more.
Many nano/microparticles (n/µP), to which our body is exposed, have no physiological way of removal. Our immune system sense these “small particulate objects”, and tries to decrease their harmfulness. Since oxidation, phagocytosis and other methods of degradation do not work with small, chemically resistant, and hydrophobic nanoparticles (nP). This applies to soot from air pollution, nano-diamonds from cosmic impact, polishing and related machines, synthetic polymers, and dietary n/µP. Our body tries to separate these from the surrounding tissue using aggregates from neutrophil extracellular traps (NETs). This effectively works in soft tissues where n/µP are entrapped into granuloma-like structures and isolated. The interactions of hydrophobic nanocrystals with circulating or ductal patrolling neutrophils and the consequent formation of occlusive aggregated NETs (aggNETs) are prone to obstruct capillaries, bile ducts in gallbladder and liver, and many more tubular structures. This may cause serious health problems and often fatality. Here we describe how specific size and surface properties of n/µP can activate neutrophils and lead to aggregation-related pathologies. We discuss “natural” sources of n/µP and those tightly connected to unhealthy diets. Full article
(This article belongs to the Special Issue Immune Responses to Nanomaterials for Biomedical Applications)
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Open AccessReview
Immunological and Toxicological Considerations for the Design of Liposomes
Nanomaterials 2020, 10(2), 190; https://doi.org/10.3390/nano10020190 - 22 Jan 2020
Cited by 2
Abstract
Liposomes hold great potential as gene and drug delivery vehicles due to their biocompatibility and modular properties, coupled with the major advantage of attenuating the risk of systemic toxicity from the encapsulated therapeutic agent. Decades of research have been dedicated to studying and [...] Read more.
Liposomes hold great potential as gene and drug delivery vehicles due to their biocompatibility and modular properties, coupled with the major advantage of attenuating the risk of systemic toxicity from the encapsulated therapeutic agent. Decades of research have been dedicated to studying and optimizing liposomal formulations for a variety of medical applications, ranging from cancer therapeutics to analgesics. Some effort has also been made to elucidate the toxicities and immune responses that these drug formulations may elicit. Notably, intravenously injected liposomes can interact with plasma proteins, leading to opsonization, thereby altering the healthy cells they come into contact with during circulation and removal. Additionally, due to the pharmacokinetics of liposomes in circulation, drugs can end up sequestered in organs of the mononuclear phagocyte system, affecting liver and spleen function. Importantly, liposomal agents can also stimulate or suppress the immune system depending on their physiochemical properties, such as size, lipid composition, pegylation, and surface charge. Despite the surge in the clinical use of liposomal agents since 1995, there are still several drawbacks that limit their range of applications. This review presents a focused analysis of these limitations, with an emphasis on toxicity to healthy tissues and unfavorable immune responses, to shed light on key considerations that should be factored into the design and clinical use of liposomal formulations. Full article
(This article belongs to the Special Issue Immune Responses to Nanomaterials for Biomedical Applications)
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Open AccessReview
Metal Oxide Nanoparticles in Therapeutic Regulation of Macrophage Functions
Nanomaterials 2019, 9(11), 1631; https://doi.org/10.3390/nano9111631 - 16 Nov 2019
Cited by 4
Abstract
Macrophages are components of the innate immune system that control a plethora of biological processes. Macrophages can be activated towards pro-inflammatory (M1) or anti-inflammatory (M2) phenotypes depending on the cue; however, polarization may be altered in bacterial and viral infections, cancer, or autoimmune [...] Read more.
Macrophages are components of the innate immune system that control a plethora of biological processes. Macrophages can be activated towards pro-inflammatory (M1) or anti-inflammatory (M2) phenotypes depending on the cue; however, polarization may be altered in bacterial and viral infections, cancer, or autoimmune diseases. Metal (zinc, iron, titanium, copper, etc.) oxide nanoparticles are widely used in therapeutic applications as drugs, nanocarriers, and diagnostic tools. Macrophages can recognize and engulf nanoparticles, while the influence of macrophage-nanoparticle interaction on cell polarization remains unclear. In this review, we summarize the molecular mechanisms that drive macrophage activation phenotypes and functions upon interaction with nanoparticles in an inflammatory microenvironment. The manifold effects of metal oxide nanoparticles on macrophages depend on the type of metal and the route of synthesis. While largely considered as drug transporters, metal oxide nanoparticles nevertheless have an immunotherapeutic potential, as they can evoke pro- or anti-inflammatory effects on macrophages and become essential for macrophage profiling in cancer, wound healing, infections, and autoimmunity. Full article
(This article belongs to the Special Issue Immune Responses to Nanomaterials for Biomedical Applications)
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Open AccessReview
Metallic Nanoparticles: General Research Approaches to Immunological Characterization
Nanomaterials 2018, 8(10), 753; https://doi.org/10.3390/nano8100753 - 22 Sep 2018
Cited by 3
Abstract
Our immunity is guaranteed by a complex system that includes specialized cells and active molecules working in a spatially and temporally coordinated manner. Interaction of nanomaterials with the immune system and their potential immunotoxicity are key aspects for an exhaustive biological characterization. Several [...] Read more.
Our immunity is guaranteed by a complex system that includes specialized cells and active molecules working in a spatially and temporally coordinated manner. Interaction of nanomaterials with the immune system and their potential immunotoxicity are key aspects for an exhaustive biological characterization. Several assays can be used to unravel the immunological features of nanoparticles, each one giving information on specific pathways leading to immune activation or immune suppression. Size, shape, and surface chemistry determine the surrounding corona, mainly formed by soluble proteins, hence, the biological identity of nanoparticles released in cell culture conditions or in a living organism. Here, we review the main laboratory characterization steps and immunological approaches that can be used to understand and predict the responses of the immune system to frequently utilized metallic or metal-containing nanoparticles, in view of their potential uses in diagnostics and selected therapeutic treatments. Full article
(This article belongs to the Special Issue Immune Responses to Nanomaterials for Biomedical Applications)
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Planned Papers

The below list represents only planned manuscripts. Some of these manuscripts have not been received by the Editorial Office yet. Papers submitted to MDPI journals are subject to peer-review.

Title: Metal Oxide Nanoparticles in Therapeutic Regulation of Macrophage Functions
Authors: Marina S. Dukhinova 1, Artur. Y. Prilepskii 1, Alexander A. Shtil 1,2, Vladimir V. Vinogradov 1,*
Affiliations:
1 ITMO University, Saint-Petersburg, Russian Federation
2 Blokhin National Medical Center of Oncology, Moscow, Russian Federation
Correspondence: [email protected]
Abstract: Macrophages (MΦ) are the components of the innate immune system that control a plethora
of biological processes. In response to the cues such as bacterial pathogens, MΦ can be activated towards pro-inflammatory (M1) or anti-inflammatory (M2) phenotype upon the request; however, the polarization process is often misshaped in pathologies such as in cancer or autoimmune conditions. Metal oxide nanoparticles (zinc, iron, titanium, copper, etc.) are widely used in therapeutic applications as drugs, nanocarriers, and diagnostic tools. It is known that MΦs can recognize and phagocyte nanoparticles, while the influence of MΦ-nanoparticle interaction on MΦ polarization remains unclear. In this review, we summarize the primary molecular mechanisms that drive MΦs activation phenotypes and functions in vitro and in vivo models of pathological inflammation. Also, a brief overview of metal oxide nanoparticles synthesis procedures is outlined. While often seen as simple drug transporters, metal oxide nanoparticles themselves have immunotherapeutic potential, as nanoparticles can have pro- or anti-inflammatory effect on MΦs and become essential instruments of MΦ profiling in cancer, wounds, viral and bacterial infections, and autoimmunity. MΦ-nanoparticle interactions require further investigations for precise therapeutic control and novel targets in immune-related disorders.
Keywords: metal oxide nanoparticles; macrophages; inflammation; immunotherapy

Title: Metal oxide nanoparticles enhance Toll-like receptors in vitro
Authors: Koshel E, Fakhardo A., Vasilichin V, Tsyimbal S, Anastasova E., Shtil A, Vinogradov V. *
Affiliation:
ITMO University, Saint-Petersburg, Russian Federation
Correspondence: [email protected]
Abstract: For the widespread application of nanotechnology in biomedicine, it is necessary to obtain
information about their safety. A critical problem is host immune responses to nanomaterials. It is suggested that the innate immune system is important for the interaction between cells and nanomaterials. However, there is only fragmentary data on the innate immune system activation by some nanoparticles (NPs). In this study, we investigated Toll-like receptors activation by clinically relevant and promising NPs such as Fe3O4, TiO2, ZnO, CuO, Ag2O and AlOOH. Cytotoxicity and effects on innate immunity factors were studied in THP-1 cell culture. NPs caused an increase in the expression of Toll-like receptors 4 and 6 to varying degrees. This suggests that the studied NPs can stimulate the innate immune system response inside the host. The data obtained should be taken into account in future research and to create safe-by-design biomedical nanomaterials.

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