Synthetic biomarkers： a twenty- first century path to early cancer detection

Kwong GA， Ghosh S， Gamboa L， Patriotis C， Srivastava S， Bhatia SN。 Synthetic biomarkers： a twenty-first century path to early cancer detection。 Nat Rev Cancer。 2021 Sep 6。

Corresponding author：gkwong@gatech。edu； ghoshjanjigias@mail。nih。gov； srivasts@mail。nih。gov；

Detection of cancer at an early stage when it is still localized improves patient response to medical interventions for most cancer types。 The success of screening tools such as cervical cytology to reduce mortality has spurred significant interest in new methods for early detection （for example， using non- invasive blood- based or biofluid- based biomarkers）。 Yet biomarkers shed from early lesions are limited by fundamental biological and mass transport barriers — such as short circulation times and blood dilution — that limit early detection。 To address this issue， synthetic biomarkers are being developed。 These represent an emerging class of diagnostics that deploy bioengineered sensors inside the body to query early- stage tumours and amplify disease signals to levels that could potentially exceed those of shed biomarkers。 These strategies leverage design principles and advances from chemistry， synthetic biology and cell engineering。 In this Review， we discuss the rationale for development of biofluid- based synthetic biomarkers。 We examine how these strategies harness dysregulated features of tumours to amplify detection signals， use tumour- selective activation to increase specificity and leverage natural processing of bodily fluids （for example， blood， urine and proximal fluids） for easy detection。 Finally， we highlight the challenges that exist for preclinical development and clinical translation of synthetic biomarker diagnostics。

在癌症仍處於區域性狀態時的早期檢測，可以提高患者對大多數癌症型別的醫療干預的響應。宮頸細胞學等篩查工具在降低死亡率方面的成功，激發了人們對早期檢測新方法的極大興趣（例如，使用非侵入性的基於血液或生物體液的生物標誌物）。然而，從早期病變中脫落的生物標誌物受到基本的生物和物質運輸障礙的限制——例如迴圈時間短和血液稀釋——從而限制了早期檢測。為了解決這個問題，人們正在開發合成生物標誌物。這代表了一類新興的診斷方法，即在體內部署生物工程感測器來查詢早期腫瘤，並將疾病訊號放大到可能超過脫落生物標誌物的水平。這些策略利用了化學、合成生物學和細胞工程的設計原理和進展。在這篇綜述中，我們討論了開發基於生物流體的合成生物標誌物的基本原理。我們研究了這些策略如何利用腫瘤的失調特徵來放大檢測訊號，使用腫瘤選擇性啟用來增加特異性，並利用體液（例如，血液、尿液和近端液體）的自然處理來易於檢測。最後，我們強調了合成生物標誌物診斷的臨床前開發和臨床轉化存在的挑戰。