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: closed (15 October 2020).

Special Issue Editor

Dr. Giuseppe Bardi
E-Mail Website
Guest Editor
Nanobiointeractions & Nanodiagnostics, Istituto Italiano di Tecnologia, Via Morego 30, 16163 Genova, Italy
Interests: Innate immune system; chemokines; nanomaterials; nanobiointeractions;adjuvants
Special Issues and Collections in MDPI journals

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

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Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2200 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 (12 papers)

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Editorial

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Editorial
Immune Responses to Nanomaterials for Biomedical Applications
Nanomaterials 2021, 11(5), 1241; https://doi.org/10.3390/nano11051241 - 08 May 2021
Viewed by 286
Abstract
The present Special Issue hosts six research papers and five review articles regarding different aspects of nanotechnologies for therapeutic and diagnostic applications [...] Full article
(This article belongs to the Special Issue Immune Responses to Nanomaterials for Biomedical Applications)

Research

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Article
CXCL12-PLGA/Pluronic Nanoparticle Internalization Abrogates CXCR4-Mediated Cell Migration
Nanomaterials 2020, 10(11), 2304; https://doi.org/10.3390/nano10112304 - 20 Nov 2020
Cited by 2 | Viewed by 687
Abstract
Chemokine-induced chemotaxis mediates physiological and pathological immune cell trafficking, as well as several processes involving cell migration. Among them, the role of CXCL12/CXCR4 signaling in cancer and metastasis is well known, and CXCR4 has been often targeted with small molecule-antagonists or short CXCL12-derived [...] Read more.
Chemokine-induced chemotaxis mediates physiological and pathological immune cell trafficking, as well as several processes involving cell migration. Among them, the role of CXCL12/CXCR4 signaling in cancer and metastasis is well known, and CXCR4 has been often targeted with small molecule-antagonists or short CXCL12-derived peptides to limit the pathological processes of cell migration and invasion. To reduce CXCR4-mediated chemotaxis, we adopted a different approach. We manufactured poly(lactic acid-co-glycolic acid) (PLGA)/Pluronic F127 nanoparticles through microfluidics-assisted nanoprecipitation and functionalized them with streptavidin to docking a biotinylated CXCL12 to be exposed on the nanoparticle surface. Our results show that CXCL12-decorated nanoparticles are non-toxic and do not induce inflammatory cytokine release in THP-1 monocytes cultured in fetal bovine and human serum-supplemented media. The cell internalization of our chemokine receptor-targeting particles increases in accordance with CXCR4 expression in FBS/medium. We demonstrated that CXCL12-decorated nanoparticles do not induce cell migration on their own, but their pre-incubation with THP-1 significantly decreases CXCR4+-cell migration, thereby antagonizing the chemotactic action of CXCL12. The use of biodegradable and immune-compatible chemokine-mimetic nanoparticles to reduce cell migration opens the way to novel antagonists with potential application in cancer treatments and inflammation. Full article
(This article belongs to the Special Issue Immune Responses to Nanomaterials for Biomedical Applications)
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Article
Harnessing the Activation of Toll-Like Receptor 2/6 by Self-Assembled Cross-β Fibrils to Design Adjuvanted Nanovaccines
Nanomaterials 2020, 10(10), 1981; https://doi.org/10.3390/nano10101981 - 07 Oct 2020
Cited by 3 | Viewed by 676
Abstract
Protein fibrils characterized with a cross-β-sheet quaternary structure have gained interest as nanomaterials in biomedicine, including in the design of subunit vaccines. Recent studies have shown that by conjugating an antigenic determinant to a self-assembling β-peptide, the resulting supramolecular assemblies act as an [...] Read more.
Protein fibrils characterized with a cross-β-sheet quaternary structure have gained interest as nanomaterials in biomedicine, including in the design of subunit vaccines. Recent studies have shown that by conjugating an antigenic determinant to a self-assembling β-peptide, the resulting supramolecular assemblies act as an antigen delivery system that potentiates the epitope-specific immune response. In this study, we used a ten-mer self-assembling sequence (I10) derived from an amyloidogenic peptide to biophysically and immunologically characterize a nanofibril-based vaccine against the influenza virus. The highly conserved epitope from the ectodomain of the matrix protein 2 (M2e) was elongated at the N-terminus of I10 by solid phase peptide synthesis. The chimeric M2e-I10 peptide readily self-assembled into unbranched, long, and twisted fibrils with a diameter between five and eight nm. These cross-β nanoassemblies were cytocompatible and activated the heterodimeric Toll-like receptor (TLR) 2/6. Upon mice subcutaneous immunization, M2e-fibrils triggered a robust anti-M2e specific immune response, which was dependent on self-assembly and did not require the use of an adjuvant. Overall, this study describes the efficacy of cross-β fibrils to activate the TLR 2/6 and to stimulate the epitope-specific immune response, supporting usage of these proteinaceous assemblies as a self-adjuvanted delivery system for antigens. Full article
(This article belongs to the Special Issue Immune Responses to Nanomaterials for Biomedical Applications)
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Article
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 8 | Viewed by 1532
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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Communication
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
Cited by 10 | Viewed by 1411
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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Article
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 8 | Viewed by 1675
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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Article
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 9 | Viewed by 2108
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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Review
Neutrophils as Main Players of Immune Response towards Nondegradable Nanoparticles
Nanomaterials 2020, 10(7), 1273; https://doi.org/10.3390/nano10071273 - 29 Jun 2020
Cited by 5 | Viewed by 1165
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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Review
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 30 | Viewed by 1633
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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Review
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 18 | Viewed by 2215
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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Review
Metallic Nanoparticles: General Research Approaches to Immunological Characterization
Nanomaterials 2018, 8(10), 753; https://doi.org/10.3390/nano8100753 - 22 Sep 2018
Cited by 9 | Viewed by 1536
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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Other

Technical Note
A Guide for Using Transmission Electron Microscopy for Studying the Radiosensitizing Effects of Gold Nanoparticles In Vitro
Nanomaterials 2021, 11(4), 859; https://doi.org/10.3390/nano11040859 - 27 Mar 2021
Cited by 2 | Viewed by 630
Abstract
The combined effects of ionizing radiation (IR) with high-z metallic nanoparticles (NPs) such as gold has developed a growing interest over the recent years. It is currently accepted that radiosensitization is not only attributed to physical effects but also to underlying chemical and [...] Read more.
The combined effects of ionizing radiation (IR) with high-z metallic nanoparticles (NPs) such as gold has developed a growing interest over the recent years. It is currently accepted that radiosensitization is not only attributed to physical effects but also to underlying chemical and biological mechanisms’ contributions. Low- and high-linear energy transfer (LET) IRs produce DNA damage of different structural types. The combination of IR with gold nanoparticles may increase the clustering of energy deposition events in the vicinity of the NPs due to the production mainly of photoelectrons and Auger electrons. Biological lesions of such origin for example on DNA are more difficult to be repaired compared to isolated lesions and can augment IR’s detrimental effects as shown by numerous studies. Transmission electron microscopy (TEM) offers a unique opportunity to study the complexity of these effects on a very detailed cellular level, in terms of structure, including nanoparticle uptake and damage. Cellular uptake and nanoparticle distribution inside the cell are crucial in order to contribute to an optimal dose enhancement effect. TEM is mostly used to observe the cellular localization of nanoparticles. However, it can also provide valuable insights on the NPs’ radiosensitization pathways, by studying the biochemical mechanisms through immunogold-labelling of antigenic sites at ultrastructural level under high resolution and magnification. Here, our goal is to describe the possibilities, methodologies and proper use of TEM in the interest of studying NPs-based radiosensitization mechanisms. Full article
(This article belongs to the Special Issue Immune Responses to Nanomaterials for Biomedical Applications)
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