Tuning ferroptosis-like, cancer-selective cell death with charge-imbalanced nanoparticles

Abstract It is known that nanoparticles functionalized with mixed charge monolayers – that is, monolayers composed of both positively [+] and negatively [-] charged ligands – can induce selective death of cancer cells. Remarkably, however, when the ligand polarities and proportions are kept constant, but the chemical nature of the “minority” [-] component is altered, the nanoparticles exhibit distinct intracellular localization patterns and induce different forms of iron-dependent lipid-peroxidation-driven cell death, which we term “ferroptosis-like” due to concurrent activation of caspases. In particular, changing the end groups on the [-] ligands from carboxylic to sulfonic to phosphonic acid shifts nanoparticle accumulation from lysosomes to autophagic compartments to late endosomes, respectively. These distinct cellular outcomes are accompanied by marked differences in the composition of serum protein coronas adsorbed onto the mixed-charge nanoparticles. Proteomic analysis revealed exceedingly complex corona proteomes, comprising more than 800 different proteins, many enriched hundreds- to thousands-fold compared to blood serum, with numerous proteins selectively enriched on specific nanoparticle types. Together, these findings identify charge-imbalanced constructs as potential modulators of subcellular organelle targeting and ferroptosis-like cell death.