Natural long-chain saturated fatty acids doped LNPs enabling spleen selective mRNA translation and potent cancer immunotherapy

Rationally tailored lipid nanoparticles(LNPs)with efficient and tunable delivery of mRNA in vivo are crucial for mRNA vaccines.Selective expression of antigenic protein in lymphoid tissues/organs could improve the immunostimulatory efficacy and safety of LNPs-based mRNA vaccines.Inspired by the metabolic behavior that long-chain saturated fatty acids tending to enter lymphoid tissue rather than the liver,we developed fatty acid-doped LNPs capable of mediating differential protein expressions in the liver and spleen when administered intravenously.When the molar ratio of saturated fatty acid located 60%–70%,the doped LNPs achieved the spleen selective mRNA translation.The mechanism could be attributed to the different cellular uptake behaviors of saturated fatty acids in hepatocytes.Immunization with a model antigen(ovalbumin)mRNA-loaded spleen selective LNPs,we observed enhanced antigen-specific T cell immune responses,and potent immunotherapeutic and immunoprophylactic efficacy in the mouse lymphoma model.Our natural long-chain saturated fatty acids metabolic characteristics-inspired design of LNPs for spleen-selective mRNA vaccines delivery will provide references for designing mRNA vaccines with high efficacy and safety for tumor immunotherapy.

SARS-CoV-2 immunity and functional recovery of COVID-19 patients 1-year after infection

The long-term immunity and functional recovery after SARS-CoV-2 infection have implications in preventive measures and patient quality of life.Here we analyzed a prospective cohort of 121 recovered COVID-19 patients from Xiangyang,China at 1-year after diagnosis.Among them,chemiluminescence immunoassay-based screening showed 99%(95%CI,98–100%)seroprevalence 10–12 months after infection,comparing to 0.8%(95%CI,0.7–0.9%)in the general population.Total anti-receptor-binding domain(RBD)antibodies remained stable since discharge,while anti-RBD IgG and neutralization levels decreased over time.A predictive model estimates 17%(95%CI,11–24%)and 87%(95%CI,80–92%)participants were still 50%protected against detectable and severe re-infection of WT SARS-CoV-2,respectively,while neutralization levels against B.1.1.7 and B.1.351 variants were significantly reduced.All non-severe patients showed normal chest CT and 21%reported COVID-19-related symptoms.In contrast,53%severe patients had abnormal chest CT,decreased pulmonary function or cardiac involvement and 79%were still symptomatic.Our findings suggest long-lasting immune protection after SARS-CoV-2 infection,while also highlight the risk of immune evasive variants and long-term consequences for COVID-19 survivors.