{"doi":"10.1101/2025.01.16.633434","title":"Development of conditional-siRNA programmable riboswitch for targeting adverse cardiac remodeling","abstract":"ABSTRACT Heart Failure (HF) remains a global epidemic and a significant healthcare burden, with an unmet need for novel therapies to target the preceding pathological hypertrophy in vulnerable patients. Here we report the development of novel conditional-siRNA ( Cond- siRNA) constructs that are selectively activated by disease-specific RNA biomarkers to enable cell-specific inhibition of a target disease-causing RNA. We designed a Cond- siRNA that can be activated by nppa mRNA, upregulated specifically in CMs under pathological stress, to silence the key pro-hypertrophic gene calcineurin by the effector siRNA. In cellular models including neonatal rat ventricular myocyte (NRVM) and rat cardiomyocyte cell-line (H9C2), Cond- siRNA exhibited low baseline activity in the absence of the disease biomarker but achieved targeted calcineurin silencing upon nppa mRNA induction by phenylephrine (PE)-induced stress in a two-dimensional (2D) cell culture system and pressure overload in three-dimensional (3D) heart-on a chip system. NRVM transfection with the Cond- siRNA resulted in a decreased expression of calcineurin mRNA specifically after PE or pressure-overload treatment, but not after vehicle treatment, proving nppa mRNA-specific activation of the effector siRNA against calcineurin. Specificity was confirmed as Cond- siRNA did not significantly silence calcineurin in cardiac fibroblasts and T cells, lacking nppa expression. Reduced calcineurin protein levels and NFATc1 nuclear translocation correlated with decreased NRVM hypertrophy after PE treatment, confirming Cond- siRNA’s efficacy. This study offers proof-of-concept for Cond- siRNA as a targeted therapy to mitigate hypertrophic progression, paving the way for novel HF treatments. One sentence summary Conditional-siRNA targeting adverse cardiac remodeling GRAPHICAL ABSTRACT","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2025,"id":560521,"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":0.9596,"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":251866,"name":"Ane Salvador","orcid":"0000-0002-6008-0976","position":1,"is_corresponding":false},{"id":1136258,"name":"Caleb Graham","orcid":null,"position":2,"is_corresponding":false},{"id":904921,"name":"Si‐ping Han","orcid":"0000-0002-2213-4953","position":3,"is_corresponding":false},{"id":251867,"name":"Guoping Li","orcid":"0000-0003-3874-0744","position":4,"is_corresponding":false},{"id":455437,"name":"Ramaswamy Kannappan","orcid":"0000-0001-5657-524X","position":5,"is_corresponding":false},{"id":1328283,"name":"Christopher Azzam","orcid":null,"position":6,"is_corresponding":false},{"id":861960,"name":"Michail Spanos","orcid":"0000-0003-1205-4201","position":7,"is_corresponding":false},{"id":904922,"name":"Lisa Scherer","orcid":"0000-0002-5019-171X","position":8,"is_corresponding":false},{"id":523909,"name":"Palaniappan Sethu","orcid":"0000-0002-5794-2037","position":9,"is_corresponding":false},{"id":324380,"name":"John J. Rossi","orcid":"0000-0003-1238-9335","position":10,"is_corresponding":false},{"id":80276,"name":"William A. Goddard","orcid":"0000-0003-0097-5716","position":11,"is_corresponding":false},{"id":251878,"name":"Saumya Das","orcid":"0000-0002-4521-4606","position":12,"is_corresponding":false},{"id":749903,"name":"Priyanka Gokulnath","orcid":"0000-0003-2813-330X","position":0,"is_corresponding":true}],"reference_count":35,"raw_metadata":null,"created_at":"2026-07-19T02:55:42.883572Z","pmid":null,"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":[]}