## 7 Challenges, Strategies and Outlooks  
Since the phenomenon of sweeteners' synergism became of academic concern around 80 years ago, a great deal of data have been reported on this interesting topic. However, there seems to be confusion in some ways when analyzing and categorizing this information. This is largely due to the varied aims, conditions, methods or experimental designs in these different investigations [11, 22, 32]. In the future, it is necessary to set up relatively unified criterions effective both in research and practice for the sweeteners' synergism. For instance, specific dose ranges for certain sweeteners, generally acknowledged evaluation methods and standards requirements for various sweeteners, test panels and conditions should be normalized to better define the sweeteners' synergism. Furthermore, new evaluation methods (e.g., biomimetic sensors and biosensors) could be optimized to improve the accuracy of the results of sweeteners' synergism [15, 16, 27, 28, 29]. Moreover, emphasis should be taken on the functional performances of sweeteners' synergism (e.g., decreasing the usage of specific sweeteners, improving the sensory quality and reducing the calories of sweetener mixtures) to design the distinct and optimal combinations of chemically diverse sweeteners.  
Despite several considerable proposals having been raised, the molecular mechanisms of sweeteners' synergism are still obscure, which limits the further development of the design and application of sweetener mixtures. The molecular basis for the onset of sweet perception that is dependent on the interaction between the sweetener (or mixture of sweeteners) and the sweet taste receptor is elusive due to the lack of structure of the receptor and its complexes with various sweeteners [75]. The recent breakthrough of AlphaFold in predicting GPCR structures could facilitate research on the mechanisms of interaction between the cooperative sweeteners and receptors, especially for molecular simulation studies [76]. Furthermore, with technological innovations such as cryo-electron microscopy, more and more structures of GPCRs have been solved in recent years, which could greatly promote the deciphering of the mechanisms of sweeteners' synergism at a structural basis [77, 78]. Lastly, because sweeteners' synergism is a complex psychophysical process and involves many signal transduction pathways, elucidating the molecular mechanisms of sweeteners' synergism needs further multidisciplinary cooperation of scientists in many fields such as food, structural biology, neuroscience, physiology and biochemistry [79, 80]. These efforts could jointly achieve the theoretical and practical development of sweeteners' synergism in the future, which will ultimately benefit the diet and health of human beings.  
Conceptualization, B.L.; software, C.W.; data curation, Y.L.; writing--original draft preparation, C.W.; writing--review and editing, B.L. and X.Z.; funding acquisition, B.L. and X.Z. All authors have read and agreed to the published version of the manuscript.  
This research was funded by the National Natural Science Foundation of China (31970935), the Natural Science Foundation of Shandong Province (ZR2020 KC035) and the Key Research & Development Project of Shandong Province, Major Science and Technology Innovation Project (2020 CXGC010604).  
**Institutional Review Board Statement:** Not applicable.  
**Informed Consent Statement:** Not applicable.  
**Data Availability Statement:** No new data were created or analyzed in this study. Data sharing is not applicable to this article.  
**Conflicts of Interest:** The authors declare no conflict of interest.