{"doi":"10.1101/2025.08.12.669990","title":"Toehold-VISTA: A machine learning approach to decipher programmable RNA sensor-target interactions","abstract":"RNA-based biosensors have emerged as essential tools in synthetic biology and diagnostics, enabling precise and programmable responses to diverse RNA inputs. However, the time to design, produce, and screen high-performance RNA sensors remains a critical challenge. The fundamental rules governing RNA-RNA interactions-specifically the structure-function relationships that determine sensor performance-remain poorly understood. Here, we present a method enabling versatile in-silico RNA-targeting analysis (VISTA), a machine learning-guided framework for the rapid design of RNA sensors. VISTA integrates biophysical modeling of both sensor and target RNAs with a partial least squares discriminant analysis (PLS-DA) machine learning framework. Using high-throughput experimental measurements with sequence-structure feature extraction to train predictive models, we capture the key determinants of RNA sensor performance. We find that by using toehold switches as a model RNA sensor, Toehold-VISTA successfully designs RNA sensors with improved function against SARS-CoV-2 RNA. These findings establish a broadly applicable, target-aware design strategy for accelerating RNA sensor engineering across biotechnology and diagnostic applications.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2025,"id":572229,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9499,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":275750,"name":"Alexander A. Green","orcid":"0000-0003-2058-1204","position":1,"is_corresponding":false},{"id":395846,"name":"James Robson","orcid":"0000-0003-1609-0007","position":0,"is_corresponding":true}],"reference_count":0,"raw_metadata":null,"created_at":"2026-07-19T02:57:23.653298Z","pmid":"40832290","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}