The interaction of cell-free DNA with biological particles has been linked to autoimmune diseases such as systemic lupus erythematosus, but mechanistic details are lacking. Our recent work has shown that DNA adsorbed on the surface of synthetic particles, forming a DNA "corona," leads to an enhanced immunostimulatory response in macrophages, providing a model system to understand how DNA-particle interactions may lead to autoimmune diseases. This current study provides a detailed examination of DNA (500-600 base pairs and ∼10,000 base pairs) interacting with synthetic particles (40 nm to 10 μm) and planar surfaces. Of specific interest is how DNA adsorbed on the surface of particles is resistant to degradation by DNase 1, a common nuclease. DNA-particle complexes are characterized by a colorimetric DNA concentration assay (PicoGreen), spectroscopy (NanoDrop), dynamic light scattering (DLS), confocal fluorescence microscopy, and transmission electron microscopy. These studies show that the protective effect of the particle is size dependent, with smaller (40 and 200 nm) particles providing less protection. Correlated with this lack of protection is significantly increased particle aggregation, suggesting that a DNA corona formed on the larger particles is protective, whereas particle aggregation, which dominates the smaller particles, is not protective. The formation of a single-stranded DNA corona leads to the opposite protective effect, with smaller (200 nm) particles leading to near-complete protection of DNA from nuclease degradation. Overall, this study provides an important biophysical basis for the interaction of DNA with particles with the goal of guiding future in vitro and in vivo studies of cell-free DNA and particles in autoimmune disease.