Glutathione functionalized selenium nanoparticles suppress colorectal cancer cell growth with mitochondrial dysfunction and mitophagy related remodeling

Glutathione functionalization may improve the physicochemical and biological performance of selenium nanoparticles; however, the effects of glutathione-functionalized selenium nanoparticles (GSH-SeNPs) on colorectal cancer (CRC) cells remain insufficiently defined. In this study, GSH-SeNPs were synthesized and characterized, and their short-term in vivo tolerability was preliminarily assessed in male mice and their biological effects in CRC cells were evaluated. In a 14-day preliminary tolerability assessment in male ICR mice ( n = 6 per group), repeated oral administration of GSH-SeNPs at doses up to 2 mg/kg produced no overt changes in body weight, relative organ weights, serum hepatic and renal biochemical indices, exploratory reproductive endocrine parameters, or tissue histology. In RKO and SW480 cells, GSH-SeNPs suppressed proliferation, migration, invasion, and adhesion, altered cell-cycle distribution, and increased apoptosis. Transcriptomic and metabolomic analyses in RKO cells revealed broad mitochondria-related, stress-response, and metabolic alterations, with integrated analysis highlighting mitophagy-related processes. GSH-SeNPs increased intracellular reactive oxygen species accumulation, reduced MitoTracker fluorescence, and decreased mitochondrial membrane potential in both cell lines. In RKO cells, GSH-SeNPs further reduced basal respiration, ATP-linked respiration, maximal respiration, spare respiratory capacity, and intracellular ATP levels, accompanied by mitochondrial ultrastructural injury. Increased mitochondrial PINK1 and Parkin protein levels and the LC3B-II/LC3B-I ratio, together with reduced TOMM20 expression, were consistent with alterations in PINK1/Parkin-associated mitophagy-related signaling. Collectively, these findings indicate that GSH-SeNPs suppress malignant phenotypes in CRC cells in association with mitochondrial dysfunction and alterations in mitophagy-related signaling. These results provide a basis for further investigation, although the absence of non-functionalized SeNP and free GSH controls and the exploratory nature of the cross-omics correlation analysis should be considered when interpreting the mechanistic findings.