Current Bionanotechnology (Discontinued) - Volume 2, Issue 1, 2016

The immune system recognizes non-self-entities and decides whether they present a danger that requires defensive action. This is, for practical purposes, an assessment of nanosafety. The intense interaction between immune system components and nanoparticles also suggests a fruitful perspective for medical exploitation.

The complement system is a central constituent of innate immunity orchestrating and bridging various responses during immune and inflammatory reactions. As such, the role of complement system in nanomedicine, in terms of functionality and performance, is multifaceted. This commentary considers the role of complement in regulation and synchronization of 1) nanoparticle opsonisation and macrophage clearance, 2) nanoparticle adjuvanticity, 3) nanomedicine-mediated acute injection reactions and 4) cancer progression on nanoparticle accumulation in solid tumours.

The different modes in which small and large molecules can be associated to a nanoparticle surface, either covalently or loosely linked, in an ordered or disordered fashion, and with mixtures of other molecules, play a determining role in the nature of the interactions between nano-objects and the immune system. The immune system may detect or not detect the nanoparticles, and tolerate them or initiate a defensive response, due to the nanoparticles themselves, to bystanders, sometime pollutants, or secondary effects, as those induced by the corrosion of the nanoparticle and the concomitant release of cations. In vitro, this can be translated in the acquisition of effector functions, such as the synthesis of cytokines, or in a lack of effect, if the NPs pass undetected.

Allergic diseases are among the most prevalent immune-mediated diseases, with incidences of well over 20% of the population in industrialized countries. Nevertheless, the question of whether allergies should be considered as a risk factor for exposure to nanomaterials has rarely been addressed. Experimental studies have attempted to improve allergy therapy by combining allergens with various nanomaterials, which may lead to a beneficial re-direction of the immune system. Binding to nanoparticles may for allergens – as for other proteins – lead to structural changes or modification of other properties. We assess here the state of knowledge about biological effects deriving from the combination of nanoparticles with allergens.

The immune response of the host tissue to the tested biomaterial predicts the success of implantation therapy success. Connective tissue cell line SaOS-2 and mononuclear cells isolated from “buffy coat” testing determines the overall immune response to the implanted biomaterial. Alginate hydrogel coatings doped with inorganic hydroxyapatite (Ti/Alg/HAP) or beta-tricalcium phosphate (Ti/Alg/TCP) nanoparticles on Titanium grade 2 were prepared. Both cell types mentioned above were used to evaluate the cytokine production when cultivated on the proposed coatings. The pristine Ti and alginate (Alg) served as control surfaces. Cytokine production was assessed by the multiplex proteomic analysis of 40 cytokines. Mononuclear cell testing revealed differences between control (Ti, Ti/Alg) and alginate hydrogel surfaces doped with calcium phosphates (Ti/Alg/TCP and Ti/Alg/HAP). Cytokine production declines from the highest found on the mononuclear cells treated by Ti/Alg/HAP through control Ti and Ti/Alg/TCP surface to control Ti/Alg surface with lowest cytokine production. Mononuclear cells produced mostly IL-6 and IL-8. No significant differences between Ti/Alg/TCP and Ti/Alg/HAP were found in cytokines produced by cell line SaOS-2. Cell line SaOS-2 produced a wide spectrum of cytokines, but the production was low, with the exception of TIMP-2. The comparison of cytokines produced by cell line SaOS-2 and mononuclear cells from “buffy coat” indicated that mononuclear cells have much better potential to show differences between the monitored materials. The immune response of mononuclear cells showed differences between tested materials, whereas SaOS-2 cells were not sufficiently sensitive. Therefore, besides SaOS-2 cells, mononuclear cells should also be considered for in vitro evaluation of overall immune response induced by the presence of an implant.

Nanotechnologies in medicine play a growing role in the development of innovative vaccines and therapeutic immunomodulatory agents. By varying their composition, size, shape, and surface properties, it is possible to obtain a vast range of nanocarriers highly efficient in targeting specific organs, tissues or cells for diagnostic and therapeutic purposes. Antibodies, anti-inflammatory drugs, adjuvants, DNA, proteins and peptides can be loaded on nanocarriers and delivered to target sites, overcoming limitations associated with recognition by innate immune cells (phagocytes), bio distribution, physical barriers, and so on. Recent evidence has highlighted the involvement of the inflammatory response in the pathogenesis of many different diseases (from neurodegeneration, autoimmunity and atherosclerosis to respiratory diseases, chronic inflammatory diseases and cancer) and on the pivotal role of macrophages. On this basis, new nanodrugs are being designed, able to specifically modulate the functional activity of these immune cells. Macrophage polarisation/plasticity and macrophage “memory” are key immunological functions in health and disease that could be modulated by innovative nanodelivery systems for preventive and therapeutic strategies.

The widespread and increasing use of engineered nanomaterials (ENMs) increases the risk of exposure by human beings. This notion has generated concern that ENMs may give rise to adverse health effects. Toxicity of ENMs is determined by both physical aspects and chemical composition. The immune system may respond to ENMs, amongst others by inflammatory reactions. Among the mechanisms underlying inflammation, inflammasome activation (especially the NLRP3 inflammasome) has drawn significant attention because it can be induced by a wide range of stimuli including ENMs and it is associated with various inflammatory diseases, including lung fibrosis, obesity and type 2 diabetes. Inflammasomes are intracellular multiprotein complexes that assemble upon stimulation, resulting in the activation of caspase-1 that in turn induces the production of interleukin (IL)-1β and IL-18. These cytokines are potent mediators of inflammation. This review summarizes the literature on NLRP3 inflammasome activation by ENMs published between 2013 and 2015. Newly identified mechanisms include a role for Endoplasmic Reticulum stress in NLRP3 inflammasome activation by Ag and ZnO ENMs and an initiating role for IL-1α. Novel insights in surface functionalization with the aim of reducing NLRP3 inflammasome activation were obtained. In vitro assays for NLRP3 inflammasome activation may predict in vivo fibrogenic potency of ENMs; including such an assay in a test battery for hazard identification is advised.

Enormous progress in the field of vaccine development has moved the area from traditional vaccines using whole microorganisms to subunit vaccines containing only purified or modified antigenic proteins. The low immunogenic potentials of subunit vaccines compared to live attenuated pathogens, have prompted the research towards developing new adjuvants with the ability to mimic and enhance the innate and adaptive immune responses. Novel adjuvants formulations based on the discovery of pattern recognition receptors (PRRs), the main class of innate immunity sensors have recently gained interest. The major family of PRRs called Toll-like receptors (TLRs), which are expressed by a variety of cells and capable to induce innate immune responses and effective stimulation of transition from innate immune responses to adaptive immune responses. PRR ligands of natural and synthetic origin have been evaluated as potential adjuvants in a variety of applications including vaccine formulations. Apart from this, for generating effective and protective immune responses, targeted delivery of vaccine antigens along with PRR agonists to the desired cells is of great importance. New strategy of delivering vaccine antigens along with adjuvants using proper nano-sized materials has gained much attention during the recent years. Here we review the recent advances regarding PRR-based nano-adjuvants developments, focusing on current nano-materials based delivery system and their applications in biomedical sciences.

Infectious diseases including HIV/AIDS and tuberculosis (TB) are a major cause of deaths worldwide. These intracellular pathogens regulate the innate immune response allowing for pathogen survival, persistence and further transmission. Nanoparticles provide an opportunity for the targeted delivery of immune modulating signals to host cells, harnessing the innate immune system to eradicate infection. In this review, we briefly present key aspects of HIV-1 and TB innate immunity, and review the capability of nanomedicines in modulating the action of the innate immune system. We conclude that while several studies have provided the proof of concept of the immunomodulatory ability of nanoparticle systems, additional characterization is required to facilitate the translation to the clinic of a nanomedicine approach to these diseases.