BPS2026 – DNA-lipid nanoparticle complexes: A model system to study systemic lupus erythematosus

Systemic lupus erythematosus (SLE) is an autoimmune disorder characterized by tissue inflammation that affects millions globally. In SLE, cell-free DNA adsorbs onto the surface of extracellular vesicles (EVs) or apoptotic bodies (ABs) where it is bound by anti-DNA antibodies to form immune complexes (ICs) that trigger inflammation. To elucidate the generation and activities of particle ICs, we have developed a model system that mimics the interactions between DNA and cationic lipid nanoparticles (LNPs) that serve as an analogue to EVs or ABs. We show that DNA binds electrostatically to the surface of these LNPs, leading to LNP aggregation and the formation of a dense “DNA corona.” Smaller LNPs (>200 nm) that exhibit a greater surface area-to-volume ratio retain a greater mass of DNA in the DNA corona. More importantly, DNA that is bound to the surface of these LNPs is resistant to degradation by common nucleases such as DNase I. Systematic studies of LNP size and surface charge revealed that, although some DNA is internalized, most remain surface-bound and protected from degradation. Further, we conducted cell studies to highlight the sequestration of DNA-coated LNPs within macrophages (RAW 264.7) and conducted sandwich assays to show that TNF-α production (a key pro-inflammatory factor) in cells incubated with DNA-decorated LNPs exceeded that of cells incubated with either bare LNPs or free DNA of the same concentration by a factor of 25. These findings extend previous studies with DNA-polystyrene nanoparticles and provide mechanistic insights into how DNA-particle complexes may contribute to inflammatory processes in autoimmune diseases.