Steroid-loaded Avidin-Nucleic-Acid-Nano-Assemblies reduce hepatic fibrosis modulating Kupffer cells in primary biliary cholangitis

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.