Biodegradable targeted polymeric mRNA nanoparticles enable in vivo CD19 CAR T cell generation and lead to B cell depletion
- Manav Jain
- Savannah E. Est-Witte
- Sydney R. Shannon
- Sarah Y. Neshat
- Xinjie Yu
- Sydney Dunham
- Tina Tian
- Leonardo Cheng
- Jawaun Harris
- Maximilian F. Konig
- Stephany Y. Tzeng
- Jonathan P. Schneck
- Jordan J. Green
2026-03-11
While chimeric antigen receptor (CAR) T cell therapies have demonstrated therapeutic efficacy against B cell malignancies, widespread implementation of these therapies is hindered by a cumbersome, ex vivo manufacturing process. Delivery of CAR-encoding messenger RNA (mRNA) to endogenous T cells can generate these therapeutic cells in vivo and streamline this manufacturing workflow. To accomplish this, T cell–activating ligands were conjugated to a biodegradable polymeric mRNA nanoparticle to form T cell–targeted particles. By conjugating multiple activating ligands, T cell transfection and stimulation in vitro was increased, and greater T cell transfection and selectivity in vivo was achieved compared to an untargeted particle. These nanoparticles can flexibly encapsulate mRNA cargos and were used to deliver anti-CD19 CAR mRNA in vivo, enabling depletion of 95% of B cells in the peripheral blood and 50% depletion of splenic B cells in healthy mice. These findings regarding nanoparticle tropism and their potential therapeutic efficacy highlight the importance of this nonviral, polymeric platform to address key limitations associated with current CAR T practices.