Corona is a result of biological molecules and NANOPARTICLEs tending to each other and mainly refers to the case of proteins. The formation of non-protein corona; i. e., carbohydrate and amino acids, and identifying the variations in their biological behavior were the purposes of this paper. The current study focused on silver NANOPARTICLEs (AgNPs, 20 and 120 nm), interaction with model small biomolecules, monosaccharides (glucose and fructose), and amino acids (histidine, cysteine, and tryptophan). The study considered the formation and composition of the corona as well as the characteristics and variations of carbohydrates/amino acids affected by AgNPs. Coronas were synthesized using the chemical reduction method, and their interactions with small biomolecules were monitored using response surface methodology (RSM). The results showed that treating glucose with smaller NANOPARTICLEs (20 nm) caused an increase in their size, agglomeration and aggregation, and a decrease in their homogeneity range. In the case of larger NANOPARTICLEs (120 nm), the glucose treatment caused to increase the size to ≥ 1 μ m. Unlike glucose, fructose treatment had no influence on the size or stability of AgNPs. In the case of amino acids, cysteine, (containing the soft element of sulfur), and tryptophan (with the symmetry of electron distribution and no desire for an electron) had the strongest and weakest influence on AgNPs, respectively. Biological studies suggest that the very considerable influence on the properties of glucose in the AgNPs environments is growing. Corona formation influences the chemical properties as well as the biological features of biomolecules. Pichia Pasturis GS115 (a cysteine-deficient microorganism using glucose-containing growth media) in a medium containing untreated glucose and histidine treated with AgNPs, as well as the medium containing glucose treated with AgNPs and untreated histidine showed the least growth. The results may help the AgNPs toxicology and underlying biological mechanisms.