Sustainable developments of nanotechnology necessitate the exploration of structure-activity relationships (SARs) at nano-bio interfaces. While ferroptosis may contribute in the developments of some severe diseases (e.g., Parkinson’s disease, stroke and tumors), the cellular pathways and nano-SARs are rarely explored in diseases elicited by nano-sized ferroptosis inducers. Here we find that WS 2 and MoS 2 nanosheets induce an iron-dependent cell death, ferroptosis in epithelial (BEAS-2B) and macrophage (THP-1) cells, evidenced by the suppression of glutathione peroxidase 4 (GPX4), oxygen radical generation and lipid peroxidation. Notably, nano-SAR analysis of 20 transition metal dichalcogenides (TMDs) disclosures the decisive role of surface vacancy in ferroptosis. We therefore develop methanol and sulfide passivation as safe design approaches for TMD nanosheets. These findings are validated in animal lungs by oropharyngeal aspiration of TMD nanosheets. Overall, our study highlights the key cellular events as well as nano-SARs in TMD-induced ferroptosis, which may facilitate the safe design of nanoproducts.

Antimicrobial resistance (AMR) is spreading worldwide and keeps evolving to adapt to antibiotics, causing increasing threats in clinics, which necessitates the exploration of antimicrobial agents for not only killing of resistant cells but also prevention of AMR progression. However, so far, there has been no effective approach. Herein, we designed lanthanum hydroxide and graphene oxide nanocomposites (La@GO) to confer a synergistic bactericidal effect in all tested resistant strains. More importantly, long-term exposure of E. coli (AMR) to subminimum inhibitory concentrations of La@GO does not trigger detectable secondary resistance, while conventional antibiotics and silver nanoparticles lead to a 16- to 64-fold increase in tolerance. The inability of E. coli to evolve resistance to La@GO is likely due to a distinctive extracellular multitarget invasion killing mechanism involving lipid dephosphorylation, lipid peroxidation, and peptidoglycan disruption. Overall, our results highlight La@GO nanocomposites as a promising solution to combating resistant bacteria without inducing the evolution of AMR.

Three mechanisms of nanoparticle-induced ferroptosis including membrane impairment, lysosomal dysfunction and mitochondrial damage have been summarized in this review.

Antimicrobial resistance (AMR) is one of the biggest threats to the environment and health. AMR rapidly invalidates conventional antibiotics, and antimicrobial nanomaterials have been increasingly explored as alternatives. Interestingly, several antimicrobial nanomaterials show AMR-independent antimicrobial effects without detectable new resistance and have therefore been suggested to prevent AMR evolution. In contrast, some are found to trigger the evolution of AMR. Given these seemingly conflicting findings, a timely discussion of the two faces of antimicrobial nanomaterials is urgently needed. This review systematically compares the killing mechanisms and structure-activity relationships of antibiotics and antimicrobial nanomaterials. We then focus on nano-microbe interactions to elucidate the impacts of molecular initiating events on AMR evolution. Finally, we provide an outlook on future antimicrobial nanomaterials and propose design principles for the prevention of AMR evolution.

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