Periodic Reporting for period 1 - LIPIRNADO (Targeted delivery of lipid nanoparticle-mRNA formulations modified with ligand pattern to dendritic cells based on DNA origami)
Reporting period: 2023-08-01 to 2025-07-31
Cancer immunotherapy has revolutionized the treatment of various malignancies. However, current therapeutic strategies often face limitations in precision, reproducibility, and control over immune cell activation. The LIPIRNADO project aims to address these challenges by developing DNA origami-based molecular platforms to precisely modulate T cell receptor (TCR) signaling. By mimicking natural spatial arrangements of immune ligands, this project explores how nanoscale geometry and molecular crowding affect T cell activation. The ultimate objective is to pave the way for programmable, synthetic immunotherapies with higher specificity and tunability. This fundamental research contributes to EU priorities in health, innovation, and responsible technology development.
The project designed and fabricated two types of DNA origami platforms—single-layer hexagonal and double-layer polygonal nanostructures—each equipped with a single anti-CD3 Fab fragment. These nanodevices were validated by AFM, agarose gel electrophoresis, and DNA-PAINT imaging to confirm structural integrity and binding capacity. Using Jurkat NFAT-luciferase reporter cells and hPBMCs, the project demonstrated that spatial positioning and structural rigidity of Fab-bearing origami directly influenced T cell activation strength and cytokine release. The most significant finding is that DNA origami–anchored anti-CD3 Fab, even in single copies, can trigger TCR activation in a geometry-dependent manner, providing strong evidence for kinetic segregation theory in a synthetic context.
This project represents a conceptual leap in the design of nanoscale immunomodulators. Unlike traditional antibody therapies or CAR-T platforms, these DNA origami constructs offer full spatial control of ligand display and enable programmable interactions with immune receptors. The results demonstrate a previously unachievable level of precision in modulating immune signaling, validating the potential of nanotechnology in synthetic immunology. These findings support the case for further translational research, including testing in relevant in vivo or organoid models. The work opens doors for patenting geometry-specific immunomodulators and collaboration with biotech or medtech companies for therapeutic development and commercialization.