MASLD is the condition of excessive accumulation of liver fat unrelated to alcohol intake, ranging from simple steatosis to metabolic dysfunction-associated steatohepatitis (MASH). With a 25% prevalence in the general population, MASLD is currently the most common liver disease, and a major healthcare and economic burden. While hyperlipidaemia, obesity and insulin resistance are the major risk factors for MASLD and contribute to its rising prevalence, growing evidence suggests that exposure to endocrine-disrupting chemicals (EDCs) can initiate and/or cause progression of MASLD. EDC-MASLD will focus on investigating the impact of environmental exposure to EDCs on the internal exposome (metabolome, gut microbiome, epigenome, proteome, immunome) and degree of liver damage in MASLD in prospective study settings, with a focus on the period of transition to progressive stages of MASLD. EDC-MASLD is particularly focused on interactions between EDC exposure, sex, genotype, diet, socioeconomic and lifestyle factors, via the data and biosamples available in the unique European NAFLD Registry, comprising over 9,000 patients with histologically characterised MASLD. EDC exposure studies will be performed in murine models of MASLD, zebrafish models, and human 2D/3D in vitro models, with an aim to understand respective mechanisms-of-action and to develop novel EDC screening tools. The EDC-MASLD consortium has diverse and complementary expertise in the domains of hepatology, endocrinology, toxicology, exposome research, metabolomics, systems biology, environmental economics, and communications & technology research, with respective PIs being global leaders in their fields. Taken together, EDC-MASLD will significantly contribute to the actions centred on identification and mechanistic assessment of impact of EDCs, strategies to monitor and reduce exposure, and regulatory actions that could better protect human and environmental health.

Despite various existing drug delivery methods, the key challenge remains: how to deliver drugs to the desired site of therapeutic action to achieve best treatment outcome, while minimising side effects? This is even more challenging in cancer immunotherapy as a complex interplay of immune reactions need to be activated. POLYMMUNE will evaluate the technical and commercial viability of our novel polymeric nanocarrier platform (developed during my ERC Consolidator grant MyNano) for targeted drug delivery of a wide variety of diseases and therapeutics. As proof of concept, we will focus on immunotherapy delivery for metastatic melanoma. Globally ~132,000 new melanoma cases will be diagnosed each year and despite recent successes, only 50% of the patients respond to novel immunotherapies that are costly, while causing severe side effects. Coupling a commercially available antigen against metastatic melanoma to our nanocarrier will activate a broad immune response, resulting in an effective cancer vaccine that potentially targets different melanoma types, enabling off-the-shelf production. This dual action will lead to increased clinical benefit, which will come with less side effects and will be 5-10-fold cheaper than current treatments. Additionally, our conjugate is industrially scalable and thus overcome a major bottle neck of current nanocarrier-based medicine. We envision our platform technology to be used as a method of choice for drug delivery in many medical applications, such as cancer immunotherapy and neurodegenerative diseases. These applications are within reach, as depending on the modification, our conjugates can e.g. bypass the blood brain barrier and potentially be administered intranasally (nanogel). Our platform offers a highly attractive business case, as biotechnology and pharmaceutical companies heavily invest in nanoconjugates due to the need for novel drug delivery strategies.

Nearly one in six of the world's population suffered from neurological disorders, this number is expected to keep growing. Many of those central nervous system (CNS) disorders do not have still an approved therapy, mainly due to one of the most challenging barriers, the blood-brain barrier (BBB). Only 2% of small-molecule drugs and ~0% of biologic drugs can reach the brain, thus stunting the development of treatment options. In POLYBRAINT we will explore the technical and commercial feasibility of an intranasal drug delivery platform (derived from ERC consolidator MyNano) to deliver biological agents to the brain for the treatment of CNS pathologies. After an adequate functionalization, our intranasally (i.n.) administered nanocarrier can reach the brain and diffuse through to specific areas of interest (i.e. hippocampus, olfactory bulb...). POLYBRAINT aims to confirm the transport, delivery, and controlled release of a functional biological agent, establish an intellectual property strategy, and assess the future commercialization feasibility of our innovative platform. Our i.n. platform has unique properties capable to overcome the main limitations of existing approaches and can revolutionize what has been achieved so far in the field, including greater versatility, higher loading capacity and controlled-sustained drug release after rationally design bioresponsive conjugation strategies among others. Additionally, our nanocarrier can be scaled at the industrial level and thus overcome a significant bottleneck of current nanocarrier-based therapeutics. Our platform offers a highly attractive business case, as biotechnology and pharmaceutical companies heavily invest in nanomedicine due to the need for novel drug delivery strategies that can cross challenging biological barriers such as the blood-brain barrier.