Modular Chemical Barcodes Enable Pooled Screening of Multimaterial Nanoparticle Libraries via GC−MS Quantitation

Abstract Nanoparticle barcoding is a powerful approach to accelerate preclinical screening of nanotherapeutics by enabling rapid collection of high-volume data using fewer biological resources, with reduced experimental labor and fewer confounding variables across experiments. We previously introduced aryl halide-based tags (halocodes) as a barcoding technology with sensitive gas chromatography−mass spectrometry (GC−MS) detection, enabling nanoparticle tracking with minimal halocode incorporation and without measurably altering nanoparticle physicochemical properties. Building on this foundation, in this work, we developed a next generation of alkoxy-modified halocodes with tunable chemical properties that enhance encapsulation and stability within nanomaterials and extend the halocoding platform to lipid-based systems. By systematically varying halocode chemical structure and nanoparticle synthesis parameters, we established design rules governing halocode loading and retention in both polymeric nanoparticles and liposomes. We then leveraged next generation halocodes to perform a pooled in vitro screen of a mixed-core PLGA and liposomal-based nanoparticle library to identify nanoparticle core and surface chemistries with the highest affinity for ovarian cancer cells. Together, next generation halocodes provide a more modular and broadly compatible barcoding toolkit that simplifies pooled screening and supports quantitative evaluation of diverse nanocarrier libraries across biological settings.