Elemental Composition and Degradation Rate Impact the Biocompatibility of Copper Chalcogenide Nanocrystals

Copper chalcogenide nanocrystals (NCs) are promising candidates for biophotonic applications due to their tunable optical properties. Concrete methods to examine the relationship between their degradation and toxicity are necessary to enable the development of nanoconstructs with reduced toxicity. This study compares the degradation and acute cytotoxicity of three compositions of micelle-coated copper chalcogenide NCs: the fluorescent semiconductor copper indium sulfide (CuInS₂), and two plasmonic semiconductors, copper sulfide (Cu_2-<i>x</i>S) and chalcopyrite copper iron sulfide (CuFeS₂). We developed a quantitative degradation assay to assess ion release from these ultrasmall nanocrystals, revealing that while all three particles biodegrade, CuInS₂ and CuFeS₂ undergo rapid degradation in an artificial lysosomal fluid, leading to a burst release of indium and iron ions. In cellular toxicity assays, CuInS₂ exhibited a significantly higher acute cytotoxicity than Cu_2-<i>x</i>S and CuFeS₂, primarily due to indium-induced necrosis. To mitigate this toxicity, an alternative surface-binding polymer coating was introduced, effectively reducing both the degradation rate and the cytotoxicity of CuInS₂. These findings highlight the influence of both nanocrystal composition and coating chemistry in moderating the acute cytotoxicity of degradable nanocrystals, demonstrating that tuning of composition and degradation rate can be used to moderate nanoparticle toxicity.