{"doi":"10.1101/2025.10.24.684449","title":"Encoded cell-material interactions to reroute cytokine signaling for regenerative medicine","abstract":"Regenerative engineering harnesses materials science and stem cell biology to develop strategies to repair damaged and diseased tissue. Despite advances in designer materials, few techniques effectively provide auto-regulated feedback mechanisms that govern how cells sense and respond to discrete microenvironmental changes. Here, we demonstrate that the artificial, juxtacrine-like receptor synthetic Notch (synNotch) can be activated by endogenous multimeric cytokines in solution, without immobilizing materials, revealing a previously unreported activation modality and yielding up to 24-fold dynamic range. To broaden synNotch sensing to monomeric cytokines, we developed nMATRIX, a co-engineered material-cell platform that detects endogenous, soluble ligands and routes them to programmed gene circuits with spatially confined effects. nMATRIX can be tuned to recognize the interleukins IL-1β and IL-6 using synNotch receptors plus cognate biomaterials, yielding up to 68-fold dynamic range and converting these inflammatory inputs into orthogonal outputs that reprogram nearby cell phenotypes. nMATRIX functions across multiple cell types and can incorporate the synNotch-related SNIPR synthetic receptor platform. nMATRIX repurposed inflammatory signals and converted them into anti-inflammatory cues to polarize macrophages (increased CD163, CD206; decreased CD86). Thus, nMATRIX couples native soluble cues to customized cellular responses with tunable sensitivity, offering a flexible materials-based approach for self-regulating regenerative therapies.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2025,"id":579100,"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":0.9484,"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":787154,"name":"Jhanvi Sharma","orcid":"0000-0003-1985-560X","position":1,"is_corresponding":false},{"id":5840,"name":"Joanne C. Lee","orcid":"0000-0003-3747-8596","position":2,"is_corresponding":false},{"id":1427777,"name":"Nicholas F. Schulze","orcid":null,"position":3,"is_corresponding":false},{"id":1037420,"name":"Hannah J. Brien","orcid":null,"position":4,"is_corresponding":false},{"id":227124,"name":"Kevin C. Corn","orcid":"0000-0001-7632-793X","position":5,"is_corresponding":false},{"id":227125,"name":"Marjan Rafat","orcid":"0000-0002-9444-4379","position":6,"is_corresponding":false},{"id":306019,"name":"Jonathan M. Brunger","orcid":"0000-0001-7468-7982","position":7,"is_corresponding":false},{"id":1036853,"name":"Zachary M. Eidman","orcid":"0000-0002-4483-0490","position":0,"is_corresponding":true}],"reference_count":106,"raw_metadata":null,"created_at":"2026-07-19T02:58:30.282164Z","pmid":"41280063","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":[]}