Toxic metals (such as lead, cadmium, mercury or arsenic) are ubiquitous environmental pollutants that occur in the ecosystem naturally or through human activity. Ill effects are related to metal overload due to external exposure or genetic factors (disturbed copper or iron metabolism), and to the deficiency or imbalance of essential metals and metalloids in the body (iron, copper, zinc, calcium, selenium). Women and children are vulnerable groups for ill effects of metals due to specific physiological features that can result in increased metal accumulation during childbearing age, gestation, lactation, and during child growth and development. The aim of this project is an integrated assessment of exposure, biological effects, and interactions of toxic (cadmium, mercury, lead) and essential elements (iron, zinc, copper, selenium) during pregnancy/prenatal period and postnatal development. Sources of exposure will be evaluated by analysing metal content in food, soil, and selected tissues of wild animals, and using epidemiological variables in women. Metal concentrations in human placentas, in maternal and umbilical cord blood, and in organs and tissues of experimental animals exposed to toxic metal (cadmium or mercury) will serve as biomarkers of internal exposure. The effects of metal exposure will be assessed through steroid hormone concentrations in human and animal placental tissue. In experimental animals, we will also evaluate the methods for decreasing metal retention, such as supplementation with mineral (e.g. essential element selenium), vitamin (e.g. vitamin C) and/or chelation treatment (by deferoxamine, D-penicillamine, succimer, unithiol, deferiprone, or Prussian blue). The efficacy of these treatments in alleviating metal toxicity will be assessed through indicators of metal-induced oxidative stress. The proposed research will provide a new insight into the reproductive and perinatal toxicology of metals, into their toxicokinetics, and into the antidotal therapy in the young. Possibilities of research application are in public health measures, which include detection and prevention of metal exposure in vulnerable population groups, women in childbearing age and infants, as well as procedures for reduction of toxic metal body retention in postnatal period.

Engineered nanomaterials (ENMs) are covered by REACH/CLP regulations; the general opinion is that the risk assessment (RA) approach routinely used for conventional chemicals is also applicable to ENMs. However, as acknowledged by OECD and ECHA, the OECD and ISO Test Guidelines (TGs) and Standard Operating Procedures (SOPs) need to be verified and adapted to be applicable to ENMs. RiskGONE will support the standardization and validation process for ENM by evaluating, optimizing and pre-validating SOPs and TGs and integrating them into a framework for risk governance (RG) of ENMs. The framework will comprise modular tools and will rely heavily on current strategies for the RA of conventional chemicals, complemented by methods for estimating environmental, social and economic benefits. It will incorporate ethical aspects and societal risk perception and will manage acceptable and unacceptable risks through transfer or mitigation. The focus of RiskGONE will be to produce nano-specific draft guidance documents for application to ENM RA; or, alternatively, to suggest ameliorations to OECD, ECHA, and ISO/CEN SOPs or guidelines. Rather than producing assays and methods ex novo, this will be achieved through Round Robin exercises and multimodal testing of OECD TGs and ECHA methods supporting the “Malta-project”, and on methods not yet considered by OECD. This process will be accelerated by guidance documents for data storage/curation/accessibility optimisation, applied to well-characterized reference ENMs typifying the main physicochemical and toxicological features of ENMs. The conditions for a transparent and self-sustained organisational form for science-based RG, representing EU stakeholders, member states, industry and civil society, will be established. The RG framework and methods developed by RiskGONE will be transferred to the organisational form for RG.

Glioblastoma (GB) is the deadliest primary malignant brain tumour, with a median survival of less than one year while current diagnostic methods suffer from significant limitations, leading to misdiagnosis and poor progression monitoring and are accompanied by invasive biopsy. Currently, there are no blood-based biomarkers available as support tool for GB management. A promising approach for such systems are liquid biopsies based on Extracellular Vesicles (EVs) that present a promising and minimally invasive approach. EVs act as versatile communication hubs, transporting a meticulously selected cargos that include various RNA molecules. The specific composition of EVs is influenced by their cell of origin, highlighting their potential as specific biomarkers for aggressive tumours such as GB. The NExGliO project aims for the development of multiplex biosensors for simultaneous detection on array of EVs-based ncRNAs signature specialized for GB diagnosis. This will be achieved via noble metal NPs which are frequently utilized as SERS substrates due to their strong plasmonic properties for ncRNAs detection. Supporting AI technologies will be developed to improve early-stage cancer diagnosis through ncRNA signature identifying algorithms. The NExGliO Staff Exchange brings together internationally recognised experts with complementary expertise from molecular biology, chemistry, nanotechnology, and AI to develop a robust platform for the early diagnosis and monitoring of GB, thus reducing reliance on invasive procedures and improving survival rates. The secondments and local training will synergize expertise from both academic and non-academic partners for a robust collaboration and to generate knowledge transfer between the consortium partners.The direct application of this knowledge, will enhance the potential to introduce innovative products to the market and solidify their position in the relevant sector as well as benefit the careers of the involved personnel.

Nanotechnology paves the way for innovative and efficient therapeutic and diagnostic agents and tools. Still, treatment of neurodegenerative disorders remains a challenging field due to therapeutic necessity to reach the brain by crossing the blood-brain barrier (BBB), one of the best gate-keeper. Multifunctional nanoparticles (NPs) offer new and improved platform to solve issues about efficacy, bioavailability and targeting ability by translocating drugs through the BBB. The ultimate goal of proposed project is development of multifunctional nano-enabled drug delivery systems for brain (BRaiND) for efficient and safe treatment of abnormalities that follow debilitating brain conditions linked to aging and degeneration. This will be achieved by following specific objectives: - design, preparation and characterization of BRaiND; - evaluation of BRaiND stability and fate in biological media; - mechanistic and quantitative assessment of interaction of BRaiND with BBB; - efficacy and safety profiling of BRaiND by a combined in vitro and in vivo approach. BRaiND will be based on selenium or gold NPs, stabilized with polyethylene gylcol and functionalized with proteins that target the brain receptors. Such multifunctionalized system will be loaded with model neuroactive agents to demonstrate its efficacy, quality and safety. Careful in vitro and in vivo testings will be performed including stability and interactions of BRaiND in different biological media, BBB permeability, and efficacy of targeting specific brain sites, neuroprotective activity, and safety profiling. SENDER work plan is based on validated and standardized methodologies, as well as emerging new experimental techniques. Considering the major challenges of translational research in neurodegenerative diseases, SENDER strategy is based on the Safe-by-Design approach and enabled by nanotechnological tools that analyze and manipulate biological processes at the nanoscale, where diseases initiate and progress.