# Delivering cytokine mRNA to secondary lymphoid organs for robust cancer immunotherapy

## TL;DR

A new method delivers cytokine mRNA to immune cells in lymphoid organs, improving cancer immunotherapy by mimicking natural cytokine function.

## Contribution

A scalable nanoparticle-based system delivers cytokine mRNA to monocytes in secondary lymphoid tissues, enabling sustained cytokine production.

## Key findings

- aNPs delivering IL-2 mRNA inhibited tumor growth in mouse cancer models.
- PET imaging confirmed translational potential in non-human primates.
- aNPs effectively triggered cytokine production in primary human immune cells.

## 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-mRNAIL-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.