{"doi":"10.1002/anie.202315425","title":"Senolysis Enabled by Senescent Cell‐Sensitive Bioorthogonal Tetrazine Ligation","abstract":"Although the clearance of senescent cells has been proven to slow down the aging process and promote anti-cancer chemotherapy, the development of senolytics remains challenging. Herein, we report a senolytic strategy enabled by senescent cell-sensitive bioorthogonal tetrazine ligation. Our design is based on linking dihydrotetrazine (Tz) to a galactose (Gal) moiety that serves both as a recognition moiety for senescence-associated β-galactosidase and a caging group for the control of tetrazine activity. Gal-Tz enables efficient click-release of a fluorescent hemicyanine and doxorubicin from a trans-cyclooctene-caged prodrug to detect and eliminate senescent HeLa and A549 cells over non-senescent counterparts with a 16.44 senolytic index. Furthermore, we leverage the strategy for the selective activation and delivery of proteolysis-targeting chimeras (PROTACs) as senolytics. PROTAC prodrug TCO-ARV-771 can be selectively activated by Gal-Tz and delivered into senescent HeLa and A549 cells to induce the degradation of bromodomain-containing protein 4. Senolytic PROTACs may offer an efficient way for intervention on cell senescence thanks to their unique capacity to degrade target proteins in a sub-stoichiometric and catalytic fashion. The results of this study establish the bioorthogonal tetrazine ligation approach as a viable strategy for selective removal of senescent cells.","journal":"Angewandte Chemie International Edition","year":2024,"id":418679,"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":47,"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":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":506732,"name":"Yue Dong","orcid":"0000-0002-5084-9809","position":1,"is_corresponding":false},{"id":230058,"name":"Hang Xu","orcid":"0000-0002-5847-655X","position":2,"is_corresponding":false},{"id":1207863,"name":"Alexis B. Cruickshank‐Taylor","orcid":null,"position":3,"is_corresponding":false},{"id":1207864,"name":"Jacob S. Kozora","orcid":null,"position":4,"is_corresponding":false},{"id":1207865,"name":"Baran Behpour","orcid":null,"position":5,"is_corresponding":false},{"id":332006,"name":"Wei Wang","orcid":"0000-0001-6043-0860","position":6,"is_corresponding":false},{"id":878940,"name":"Mengyang Chang","orcid":"0000-0001-9679-8616","position":0,"is_corresponding":true}],"reference_count":65,"raw_metadata":null,"created_at":"2026-07-19T01:57:09.067930Z","pmid":"38233359","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":[]}