Abstract
DNA barcoding is a common method for identifying the biodistribution of nanoparticles. DNA barcodes are typically encapsulated within nanoparticles to ensure accurate measurements by next-generation sequencing. This method limits the types of nanoparticles that can be screened. DNA can also be coated on nanoparticle surfaces. However, it is unclear whether surface-coated DNA can be used as barcodes because they can degrade, making the identification and quantification of nanoparticle designs challenging. Here, we developed strategies to reduce DNA degradation on nanoparticle surfaces, allowing surface-based DNA barcodes for biodistribution applications. We demonstrate that nanoparticle size, DNA density, and polymer length and density are essential design parameters for accurately identifying and quantifying nanoparticles in vivo. We found that chemical modification of DNA and shielding using neutral polymers reduce DNA degradation. We validated that surface barcoding can determine the in vivo distribution of nanoparticles. Our findings pave the way for the use of surface-based DNA barcodes for in vivo screening of nanoparticle formulations for targeted applications.