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Future climate CO 2 (eCO 2) and contamination with nano-sized heavy metals (HM-NPs) represent concurrent challenges threatening plants. The interaction between eCO 2 and HM-NPs is rarely investigated, and no study has addressed their synchronous impact on the metabolism of the multifunctional stress-related metabolites, such as sugars and amino acids. Moreover, the characteristic responses of C3 and C4 plant systems to the concurrent impact of eCO 2 and HM-NPs are poorly understood. Herein, we have assessed the impact of eCO 2 (620 ppm) and/or HgO-NPs (100 mg/Kg soil) on growth, physiology and metabolism of sugars and amino acids, particularly proline, in C3 (wheat) and C4 (maize) plant systems. Under Hg-free conditions, eCO 2 treatment markedly improved the growth and photosynthesis and induced sugars levels and metabolism (glucose, fructose, sucrose, starch, sucrose P synthase and starch synthase) in wheat (C3) only. In contrast, HgO-NPs induced the uptake, accumulation and translocation of Hg in wheat and to less extend in maize plants. Particularly in wheat, this induced significant decreases in growth and photosynthesis and increases in photorespiration, dark respiration and levels of tricarboxylic acid cycle organic acids. Interestingly, the co-application of eCO 2 reduced the accumulation of Hg and recovered the HgO-NPs-induced effects on growth and metabolism in both plants. At stress defense level, HgO-NPs induced the accumulation of sucrose and proline, more in maize, via upregulation of sucrose P synthase, ornithine amino transferase, ∆1-pyrroline-5-carboxylate (P5C) synthetase and P5C reductase. The co-existence of eCO 2 favored reduced sucrose biosynthesis and induced proline catabolism, which provide high energy to resume plant growth. Overall, despite the difference in their response to eCO 2 under normal conditions, eCO 2 induced similar metabolic events in C3 and C4 plants under stressful conditions, which trigger stress recovery. Unlabelled Image • Under HgO-NPs free conditions, the biofertilization impact of eCO 2 is only evident in wheat (C3). • HgO-NPs increased Hg uptake, accumulation and translocation in the tested plants. • Maize plants (C4) were more tolerant to HgO-NPs toxicity than wheat. • HgO-NPs induced the accumulation of sucrose and proline, more in maize. • Coexistence of eCO 2 with HgO-NPs reduced sucrose biosynthesis and induced proline catabolism in both plants. [ABSTRACT FROM AUTHOR]