近日，美国斯坦福大学医学院Das, Rhiju团队报道了紧凑型RNA传感器用于日益复杂的多输入功能。该项研究成果发表在2025年11月12日出版的《自然-化学》杂志上。

设计能够计算输入分子通用函数的单个分子，是分子设计领域一个尚未攻克的重要挑战。研究组证明，通过对在线游戏Eterna众包设计的多种RNA进行高通量迭代实验测试，可实现对输入寡核苷酸浓度日益复杂函数的传感检测。

在成功设计出激活比超出检测极限的单输入RNA传感器后，研究组进一步创建了逻辑门（包括具有挑战性的异或门和同或门）以及能响应双输入比值的传感器。最后，研究组详细介绍了OpenTB挑战赛——该赛事成功研发出能基于三个基因片段产物比值计算活动性肺结核诊断评分的85核苷酸传感器。基于OpenTB的设计策略，研究组开发了Nucleologic算法，可针对RNA和DNA的三基因评分生成同样紧凑的传感器。这些成果拓展了紧凑型单分子传感器在诸多领域的应用前景，这些领域以往常因设计复杂性而受限。

附：英文原文

Title: Compact RNA sensors for increasingly complex functions of multiple inputs

Author: Choe, Christian A., Andreasson, Johan O. L., Melaine, Feriel, Kladwang, Wipapat, Wu, Michelle J., Portela, Fernando, Wellington-Oguri, Roger, Nicol, John J., Wayment-Steele, Hannah K., Gotrik, Michael, Khatri, Purvesh, Greenleaf, William J., Das, Rhiju

Issue&Volume: 2025-11-12

Abstract: Designing single molecules that compute general functions of input molecular partners is a major unsolved challenge in molecular design. Here we demonstrate that high-throughput, iterative experimental testing of diverse RNA designs crowdsourced from the online game Eterna yields sensors of increasingly complex functions of input oligonucleotide concentrations. After designing single-input RNA sensors with activation ratios beyond our detection limits, we created logic gates, including challenging XOR and XNOR gates, and sensors that respond to the ratio of two inputs. Finally, we describe the OpenTB challenge, which elicited 85-nucleotide sensors that compute a score for diagnosing active tuberculosis based on the ratio of products of three gene segments. Building on OpenTB design strategies, we created an algorithm, Nucleologic, that produces similarly compact sensors for the three-gene score based on RNA and DNA. These results expand the possibilities for using compact, single-molecule sensors in a range of applications previously constrained by design complexity.

DOI: 10.1038/s41557-025-01907-8

Source: https://www.nature.com/articles/s41557-025-01907-8