In the ongoing battle against cancer, researchers have been striving for an ideal treatment method—one that can accurately eliminate tumor cells without harming healthy tissues.
A recent breakthrough by Professor Hai-Feng Ye's team from the School of Life Sciences at East China Normal University and the Key Laboratory of Regulatory Biology in Shanghai brings us closer to achieving this goal. They propose an innovative approach to cancer treatment—utilizing ultrasound-controlled cell "biobombs" to launch precise attacks against tumors. On April 11, their findings were published in Cell Reports Medicine.
With the rapid development of synthetic biology, an intelligent microbial delivery system has emerged, offering new hope for precise treatments of diseases like cancer. These intelligent microbes act as miniature drug factories, capable of sensing predetermined signals within the body, such as inflammation, infection, and tumors, and responding accurately.
It's worth noting that some microbes naturally have an affinity for tumor tissues, able to colonize and thrive in the tumor microenvironment characterized by low oxygen, high acidity, and immune suppression. They possess inherent anti-tumor effects, making them ideal carriers for delivering anti-cancer drugs. However, in existing technologies, the continuous expression of drug proteins may inhibit the growth of the microbes themselves and potentially harm healthy tissues. Moreover, traditional drug delivery methods lack precise control, making it difficult to meet the requirements of precision medicine.
In their latest research, Professor Ye's team proposed a solution by employing a new tactic—sonogenetics, which involves controlling cellular behavior using ultrasound.
As a safe technique widely used in clinical diagnosis and treatment, ultrasound is given a new mission in this study. Researchers ingeniously exploited ultrasound's non-invasiveness, deep tissue penetration, and spatiotemporal specificity to develop an ultrasound-controlled gene expression system (SINGER). This system relies on a temperature-sensitive transcriptional repressor, TlpA39, capable of precisely activating the expression of specific genes in response to minor temperature changes induced by ultrasound.
They also demonstrated a novel sonogenetics-controlled customized bacterium. Under ultrasound stimulation, engineered bacteria carrying the SINGER system can locally raise the temperature to 39 degrees Celsius, efficiently initiating the expression of specific genes. This means that ultrasound can make engineered bacteria "obediently" secrete therapeutic proteins at the right time and place, achieving precise control over the expression and release of anti-tumor drugs. This spatiotemporal control mechanism ensures that the treatment directly targets tumor cells while maximizing the protection of healthy cells from harm.
Engineered bacteria can be delivered into the body via intratumoral or intravenous injection, selectively colonizing and proliferating in hypoxic and necrotic areas of tumors. Under precise ultrasound control, these "biobombs" are activated within the tumor, expressing and releasing therapeutic drugs in situ, effectively inhibiting tumor growth, and even eradicating the tumor entirely.
Schematic diagram illustrating the process of ultrasound-stimulated engineered bacteria locally producing and releasing therapeutic anti-tumor proteins within tumor tissues. Image provided by the research team.
In various mouse tumor models, this ultrasound-controlled engineered bacteria have demonstrated significant anti-tumor effects. Through direct injection into the tumor or intravenous delivery, the engineered bacteria can accurately target the tumor area and, under ultrasound induction, release potent anti-cancer proteins such as Azurin protein, which can induce apoptosis in tumor cells, directly killing them in the core region of the tumor. Additionally, researchers have explored a treatment strategy combining Azurin with the immune checkpoint inhibitor PD-L1 nb, which not only induces apoptosis in tumor cells but also activates the body's immune system, achieving a dual anti-cancer effect.
The development of the SINGER system not only provides new insights into cancer treatment but its high modularity and compatibility also make this technology potentially applicable to the treatment of various diseases. In the future, this ultrasound-controlled microbial therapy may be used to treat metabolic diseases, inflammatory diseases, or infectious diseases, providing patients with more personalized, non-invasive treatment options.
Although current technology still faces challenges in delivering more precise treatments to deep-seated or metastatic tumors, with further research and improvements in related technologies, ultrasound-controlled engineered bacterial therapy is expected to open up new frontiers in precision medicine, providing patients with more precise and safer treatment options. In the near future, ultrasound-controlled cellular "biobombs" are expected to become powerful weapons against tumors, bringing new hope to a large number of cancer patients.
Graduates from East China Normal University, Tian Gao from the class of 2023, Lingxue Niu from the class of 2022, and Xin Wu from the class of 2023, are the co-first authors of the paper. Haifeng Ye and Ningzi Guan, associate researcher at the School of Life Sciences, East China Normal University, are the co-corresponding authors of the paper.
Related paper information: https://doi.org/10.1016/j.xcrm.2024.101513
