Neutrophil extracellular traps (NETs) are networks of decondensed chromatin, histones, and antimicrobial proteins released by neutrophils in response to an infection. NET overproduction can cause an exacerbated hyperinflammatory response in a variety of diseases and can lead to host tissue damage without clearance of infection. Nanoparticle drug delivery is a promising avenue for creating materials that can both target NETs and deliver sustained amounts of NET-degrading drugs to alleviate hyperinflammation. Here, we study how particle physicochemical properties can influence NET interaction and leverage our findings to create NET-interfacing and NET-degrading particles. We fabricated a panel of particles of varying sizes (200 to 1000 nm) and charges (positive, neutral, negative) and found that positive charge is the main driver of NET-particle interaction, with smaller 200 nm positive particles having a 10-fold increase in binding compared to larger 1000 nm positive particles. Negative and neutral particles were mostly noninteracting, except for small negatively charged particles that exhibited very low levels of NET localization. Interaction strength of particles with NETs was quantified via shear flow assays and atomic force microscopy. This information was leveraged to create DNase-loaded particles that could adhere to NETs at varying degrees and therefore degrade NETs at different rates . Positively charged, 200 nm DNase-loaded particles showed the highest degree of interaction with NETs and therefore led to faster degradation compared with larger sizes, underscoring the importance of physicochemical design for NET-targeting drug delivery. Overall, this work provides fundamental knowledge of the drivers of particle-NET interaction and a basis for designing NET-targeting particles for various disease states.