Researchers at the Shenzhen Institute of Advanced Technology (SIAT) achieved deep, tumor-targeted, photoacoustic imaging without losing signal intensity or resolution. To control interference from background signals, they developed a reporter protein with high photoswitching contrast. The protein is expressed through a bacterial carrier that homes in on the tumor region, to enable targeted photoacoustic imaging and monitoring of deep tumor tissues. Photoacoustic imaging allows researchers to go deep within biological tissue to obtain detailed molecular information. However, the detection sensitivity of photoacoustic imaging is limited by blood background signals from endogenous chromophores such as hemoglobin. Photochromism, which is the process of a substance undergoing a reversible change in color when exposed to light, can help to suppress interference from background signals. Genetic reporter proteins with photoswitchable properties enable the background signals to be removed through the subtraction of photoacoustic images for each light-absorbing form. For this approach to work in practice, however, the photoswitchable chromoproteins need to be targeted. As part of a collaboration with researchers at the University of Texas at Austin, the SIAT team integrated a genetically encoded probe with photoacoustic imaging and synthetic biology to create a photoswitchable probe that works in vivo, with high specificity, to target tumors for photoacoustic imaging. The researchers engineered a phytochrome-based reporter protein (F469W), the efficiency of which is the highest reported to date at eliminating blood background signals, they said. In reprogramming a bacterial vector (E. coli), the team was able to produce the photoswitchable chromoprotein (F469W) and deliver it to the tumor region. The F469W-expressing E. coli exhibited tumor-preferential colonization, facilitating point-specific delivery of the genetically encoded photochromic probes to the microenvironment of the tumor site for long-term, stable tumor imaging. E. coli bacteria can be treated with streptomycin, ensuring control over the use of this organism as a carrier to tumor sites. The researchers used photoacoustic computed tomography to realize deep-tissue, high-resolution, tumor-specific, in vivo imaging of mice. A schematic of the bacteria-based in vivo delivery system for photoswitchable chromoproteins. An international team developed a photoacoustic imaging approach that aims to simplify the diagnosis of tumor-related diseases, along with the ability to monitor them over the long term. The ability to image tumors at substantial depths could enable specific cancer diagnoses to be made with greater sensitivity. Courtesy of SIAT. The team calls its approach GPS imaging, where G stands for genetically encoded probe, P stands for photoacoustic imaging, and S stands for synthetic biology. The GPS imaging approach integrates these three tools to achieve background-suppressed, targeted photoacoustic monitoring in deep tissues. GPS imaging could also make it easier to diagnose tumor-related diseases and monitor them over the long term, the researchers said. The ability to image tumors at substantial depths could enable specific cancer diagnoses to be made with greater sensitivity, fidelity, and specificity. The research was published in the Proceedings of the National Academy of Sciences (PNAS) (www.doi.org/10.1073/pnas.2121982119).