Researchers have shown significant interest in three-dimensional DNA building blocks due to their potential applications in biomedicine and biosensing. This study focuses on the synthesis of an HgII ion-stabilized DNA capsule with T-HgII-T pairs for the purpose of detecting melamine (MA). MA reacts with HgII to form a MA-HgII-MA complex, which causes HgII to leave the capsule shell, ultimately leading to capsule collapse and release of fluorescent cargo asoutput signal. Density functional theory (DFT) calculations and X-ray absorption spectroscopy (XAS) were used to demonstrate the ability of MA to extract HgII from the T-HgII-T adducts. The DNA capsules were characterized using TEM, SEM, DLS, zeta-potential, and melting curve analysis, which indicated the successful construction of the HgII-intercalated DNA shell. The MA-triggered destruction of the DNA capsules was visualized by confocal microscopy, and the dynamics of decapsulation were evaluated through fluorescent cargo release. The HgII-stabilized DNA capsules enable MA detection with a detection limit of 0.037 µM and are insensitive to potential interfering ions and amino acids. The tests conducted usingMA spiked milk solution resulted in recoveries ranging from 109 to 113% (0.1 µM) and 94.5 to 96% (0.5 µM). These results suggest that the system is promising for highly accurate and reproducible monitoring of MA adulteration.