Glycogen-inspired trimannosylated serum albumin nanocarriers for targeted delivery of toll-like receptor 7/8 agonists to immune cells and liver

Nanocarriers can improve the therapeutic efficiency of small molecule immunomodulators or inhibitors, which is important for immunotherapy of liver diseases or cancer. Macromolecular protein carriers, such as human serum albumin (HSA), could provide better penetration compared to large nanoparticles (>50 nm) but are hampered by systemic biodistribution. To overcome these limitations, inspired by the natural glycogen structure, we have designed the HSA nanocarrier (<40 nm) consisting of multiple trimannose (TM) ligands attached to the protein surface, to target mannose or dendritic cell-specific intercellular adhesion molecule-3-grabbing non-integrin (DC-SIGN) receptors in immune cells or immunological organs such as the liver. Capitalizing on the chemical reactivity of different amino acids present in HSA, we have incorporated multiple copies of a cargo relevant for immunotherapy, i.e. the toll-like receptor (TLR) 7/8 agonist. The resulting TM-HSA conjugates exhibit excellent and specific uptake ex vivo in various immune cells and liver-specific uptake in vivo, opening access to protein nanocarriers with rapid and efficient in vivo targeting with great potential for immune-related diseases.