The use of nanoparticles (NPs) has surely grown in recent years due to their versatility, with a spectrum of applications that range from nanomedicine to the food industry. Recent research focuses on the development of NPs for the oral administration route rather than the intravenous one, placing the interactions between NPs and the intestine at the centre of the attention. This allows the NPs functionalization to exploit the different characteristics of the digestive tract, such as the different pH, the intestinal mucus layer, or the intestinal absorption capacity. On the other hand, these same characteristics can represent a problem for their complexity, also considering the potential interactions with the food matrix or the microbiota. This review intends to give a comprehensive look into three main branches of NPs delivery through the oral route: the functionalization of NPs drug carriers for systemic targets, with the case of insulin carriers as an example; NPs for the delivery of drugs locally active in the intestine, for the treatment of inflammatory bowel diseases and colon cancer; finally, the potential concerns and side effects of the accidental and uncontrolled exposure to NPs employed as food additives, with focus on E171 (titanium dioxide) and E174 (silver NPs).

Nonalcoholic fatty liver disease (NAFLD, including nonalcoholic fatty liver (NAFL) and nonalcoholic steatohepatitis (NASH)) is a high-prevalence disorder, affecting about 1 billion people, which can evolve to more severe conditions like cirrhosis or hepatocellular carcinoma. NAFLD is often concomitant with conditions of the metabolic syndrome, such as central obesity and insulin-resistance, but a specific drug able to revert NAFL and prevent its evolution towards NASH is still lacking. With the liver being a key organ in metabolic processes, the potential therapeutic strategies are many, and range from directly targeting the lipid metabolism to the prevention of tissue inflammation. However, side effects have been reported for the drugs tested up to now. In this review, different approaches to the treatment of NAFLD are presented, including newer therapies and ongoing clinical trials. Particular focus is placed on the reverse cholesterol transport system and on the agonists for nuclear factors like PPAR and FXR, but also drugs initially developed for other conditions such as incretins and thyromimetics along with validated natural compounds that have anti-inflammatory potential. This work provides an overview of the different therapeutic strategies currently being tested for NAFLD, other than, or along with, the recommendation of weight loss.

Primary biliary cholangitis (PBC) is the most common life-long autoimmune liver disease arising from a biliary epithelial activation to a complex evolving cascade of immune-mediated injury, leading to inflammation and fibrosis and ultimately cirrhosis and liver failure. Ursodeoxycholic acid (UDCA) remains the only first-line treatment, despite being ineffective in approximately 40% of patients. Inadequate response to UDCA has been associated with increased death risk or need for liver transplantation. Starting from these premises, novel or repurposed drugs are currently needed. Immunosuppressive therapies, such as corticosteroids, remain controversial, primarily due to safety concerns related to off-target effects and limited evidence of enhanced efficacy. Nanoparticles are known to accumulate in the liver. Among them, Avidin-Nucleic-Acids-Nano-ASsemblies (ANANAS) have emerged as promising drug carriers thanks to their multi-functionality and convenient tunability, biodegradability, biocompatibility and scalable manufacturing. Despite the availability of numerous PBC models, none replicate key features of human disease to the degree observed in ARE Del-/- mice. Focusing on this model, ANANAS loaded with acid-releasable dexamethasone (ANANAS-Hz-Dex-M) were parenterally administered to evaluate distribution, pharmacokinetics, and therapeutic efficacy. The single treatment demonstrated selective liver tropism with an exclusive steroid release, and interaction with resident macrophages. Multiple administrations significantly reduced hepatic fibrosis. In vitro, isolated Kupffer cells from ARE Del-/- internalize the nanoassembly, with a reduction of the inflammatory profile. Our findings delineate ANANAS-Hz-Dex-M as a tool with the potential to guide resident macrophage plasticity and ameliorate disease course.