Mechanistic Dissection and Rational Design of Lipid Nanoparticle–Immune Interactions for Safe T Cell Therapy in Autoimmunity

• Applicant: Norman Michael Drzeniek, Ph.D.
• Subject Area: Immunology ; Biomaterials ; Cell Biology
• Term: since 2026
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 577345518

This project explores how an emerging class of nano drugcarriers, called lipid nanoparticles (LNPs), interact with immune cells, to make T cell therapies safer and more effective for patients with autoimmune diseases. Early generation mRNA-LNP formulations used in SARS-CoV2 vaccines have demonstrated a favorable efficacy and safety profile in a global population but have also been shown to promote flares of autoimmune disease in predisposed individuals. An important emerging application of LNPs is the engineering of chimeric antigen receptor (CAR) T cells ex vivo and in vivo, particularly for the treatment of autoimmune disease. This poses a dilemma, where systemic LNP-triggered inflammation may exacerbate the disease, while cell-intrinsic responses may impact CAR T cells in ways which are not understood. The biological mechanisms behind LNP-cell interaction are incompletely understood; as is the structure function relationship between LNP lipid design and inflammation, hindering rational design of "non-inflammatory" LNPs. To address this, the project pursues three main goals: 1. An understanding of the impact of LNP chemistry on (CAR-)T cell phenotype and function: Leading LNP candidates for T cell transfection use next-generation lipids with defined structural features, which owe their high transfection efficacy to effective endosomal escape. At the same, endosomal rupture is discussed to drive cell-intrinsic inflammation and many of these novel lipid classes have been described as proinflammatory in other contexts. I will systematically characterize the relationship between ionizable lipid chemistries and cellular responses and investigate the role of endosomal rupture and repair in LNP-T cell transfection. 2. Explore targeted LNPs: For in vivo CAR T manufacturing antibody-targeted LNPs are being explored, which are taken up upon binding a T cell surface antigen. I will explore how their altered uptake modulates their immune interactions. 3. Understand the consequence of LNP-triggered responses for different types of systemic inflammation: I will assess systemic inflammation and toxicity toward selected LNPs in healthy, septic and autoimmune-predisposed mice and assess the impact of proinflammatory LNP formulations on murine lupus disease onset and severity. By the end of this fellowship, the project will provide a blueprint for designing non-inflammatory LNPs that are tailored for T cell therapies in autoimmunity. This knowledge will guide the safe translation of new nanomedicines into the clinic and broaden treatment options for patients with otherwise untreatable immune diseases. Beyond its immediate impact, the project builds a methodological foundation to understand how nanomaterials interact with the immune system, an area of growing importance in medicine. For my career, it will allow me to bridge clinical immunology and bioengineering, preparing me to lead future research on safe and precise therapeutic technology.

• DFG Programme: Fellowship
• International Connection: USA
• Host: Professor Michael J. Mitchell, Ph.D.