Transition metal ions and their oxide nanoparticles differentially regulate CHO cell growth, metabolism, and N-glycosylation

Abstract

Trace metal ions act as essential cofactors but exhibit concentration-dependent cytotoxicity that shapes Chinese hamster ovary (CHO) cell culture performance. This work systematically evaluated six transition metal ions (Fe3+, Mn2+, Cu2+, Zn2+, Co2+, Ni2+) and their metal oxide nanoparticles for their impacts on cell proliferation, metabolism and protein N-glycosylation. Single-metal screening revealed dose-dependent effects: low Fe3+ and Mn2+ boosted cell growth, while high Cu2+ and Zn2+ triggered severe cytotoxicity. Nanoparticles displayed milder toxicity than ionic metals owing to slow dissolution kinetics. Moderate combined supplementation of Mn2+/Fe3+ ions or as-synthesized layered double hydroxide (LDH) nanoparticles (MnFe-LDH) optimized 14-day batch culture, improving cell viability, protein yield and N-glycan galactosylation. Transcriptomic data identified mitochondrial respiratory chain as the primary responsive pathway, with six subunits of complexes I-V (COX2, COX3, ATP6, ND3, ND4, ND4L) upregulated in a dose-dependent fashion. This study offers mechanistic support for rational trace metal feeding strategies in CHO-based biopharmaceutical production, although practical translation of nanoparticle-based supplementation will additionally require control of particle dissolution behavior and removal of nanoparticle residues during downstream processing.

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