Environmental genotoxins cause DNA damage and lead to gene dysfunction and mutation, posing a serious threat to health. In this article, a styrene-7,8-oxide–responsive DNA capsule (SODC) was designed and synthesized to respond to styrene-7,8-oxide (SO) (0–2%) within 10 min. The SODC was constructed by assembling three DNA oligos in a layer-by-layer structure and forming crosslinked hybridized DNA with segmented duplexes in 7–8 bp. The duplexes contained numerous guanine–cytosine pairs that were susceptible to electrophilic attack of SO. The resulting SO–purine adducts caused duplex dehybridization, which led to collapse of the SODC and release of fluorescent cargo. The size, number, zeta potential, and morphology of the SODC were evaluated. The melting curve indicated integrity of the crosslinked hybridization, which was evident from a substantial increase in melting temperature. SO-triggered transformation of the DNA capsules was tracked using a confocal microscope. To maximize the unlocking efficiency of the SODC, the effects of incubation time, temperature, pH, and ionic concentration on the outputted fluorescence were also studied. The response yielded by styrene and toluene (2%) was minimal. The interference caused by a high concentration of K3PO4 (50 mM)—a mimicking condition of intracellular fluid—was negligible. This system presented promising DNA-encoded sensing elements in the surveillance of the effect caused by environmental genotoxins.