Albumin-recruiting lipid nanoparticle potentiates the safety and efficacy of mRNA vaccines by avoiding liver accumulation

The advent of mRNA vaccines represents a breakthrough in the realm of cancer therapy and the prevention of infectious disease. Nevertheless, traditional lipid nanoparticle (LNP)-based mRNA vaccines can accumulate in the liver post-intramuscular injection, posing a risk of hepatotoxicity and reducing efficacy. Here we develop an albumin-recruiting LNP system with high lymphatic drainage and no accumulation in hepatic tissue to potentiate the efficacy and safety of mRNA vaccines. We construct a library of ionizable lipids with albumin-binding capacity as alternatives to traditional polyethylene-glycol-conjugated lipid. We identify an Evans blue-modified lipid-based LNP (EB-LNP) formulation that shows high in vivo expression, albumin-facilitated transport through intramuscular lymphatic vessels to the lymph nodes, high internalization by dendritic cells and low penetration into intramuscular blood vessels, thereby avoiding liver accumulation. EB-LNP-based mRNA vaccines demonstrate excellent antitumour and antiviral efficacy, resulting in strong cellular and humoral immune responses, including the robust activation of cytotoxic T lymphocytes and production of neutralizing antibodies post-vaccination. Overall, this system shows promise as an effective and minimally toxic platform for the development of mRNA vaccines with high efficacy and safety.