Delivering cytokine mRNA to secondary lymphoid organs for robust cancer immunotherapy

Abstract Recombinant cytokine therapeutics, among the earliest clinical immunotherapies, have yet to reach their full potential despite bioengineering advances. Here, we propose a novel approach focusing on in vivo cytokine production by immune cells in lymphoid organs to mimic these proteins’ physiological function. We developed apolipoprotein nanoparticles (aNPs) to deliver mRNA encoding cytokines, such as interleukin-2 (IL-2), to monocytes in secondary lymphoid tissues. To this end, we engineered a scalable manufacturing process that yields stable aNP- mRNA formulations suitable for long-term storage. Intravenous aNP-mRNA-IL-2 administration in mice led to sustained IL-2 production in the spleen and lymph nodes, significantly inhibiting tumor growth in B16F10 melanoma and MC38 colon cancer models. We confirmed translational potential through clinical positron emission tomography (PET) imaging and functional cytokine production in non-human primates, and validated aNP-mRNA efficacy on primary immune cells from cancer patients. This mRNA-based cytokine delivery to lymphoid organs offers a promising strategy to enhance cytokine immunotherapy for cancer and potentially other immune-mediated diseases, including autoimmunity, cardiovascular disease, and neurodegenerative conditions.