A cross-responsive strategy (CRS) based on gold nanoparticles (AuNPs) through attaching various recognition receptors on the surface of AuNPs for identifying multiple analytes is presented, and the detection throughput and overall identification accuracy are improved. However, the CRS's recognition receptor cannot get comprehensive information from the target analytes limited in number and type, which determines the overall identification accuracy. Therefore, the practicability of the CRS runs into a bottleneck. Herein, we report a programmable DNA-AuNP encoder combined with a multimodal coupled analysis algorithm for high-throughput detection and accurate analysis of multiple metal ions. The programmable DNA-AuNP encoder breaks through the limitation of the recognition receptor's quantity. Furthermore, the multimodal signals from target metal ion-induced DNA-AuNP aggregation are related to and observed in the ultraviolet absorbance spectrum, surface potential, and particle diameter. The multimodal coupled analysis algorithm can reflect comprehensive information on the target analyte more completely. Finally, this study provides a highly generic tool for the cross-responsive strategy.