{"doi":"10.1111/cbdd.70168","title":"Morpholine‐Facilitated Enrichment‐Triggered Delivery of Carbon Monoxide to Lysosome: A Feasibility Study","abstract":"ABSTRACT Targeted delivery of carbon monoxide (CO) prodrugs holds important therapeutic potential for various applications. Along this line, we developed an enrichment‐triggered release (ETR) approach for activating 2‐component (a diene and a dienophile) CO prodrugs upon enrichment in the mitochondrion, giving a “one stone, two birds” approach. Herein, we aim to broaden the scope of application to targeted delivery to the lysosome. We tethered a CO prodrug pair, a diene and a dienophile, with morpholine, a lysosomal targeting moiety. Several analogs were synthesized to tune the second‐order rate constants ( k 2 ) to a desirable range. We chose two pairs of the prodrugs with different second‐order rate constants (0.087 and 0.21 M −1 s −1 ) to further study their enrichment and CO release ability. For one pair, LC–MS experiments revealed > 13‐fold enrichment of the morpholine‐conjugated CO prodrug pair compared to non‐targeted controls in HeLa cells. Fluorescence studies demonstrated the same enrichment and co‐localization of LysoTracker. For the second pair, conjugation with morpholine did not lead to improved enrichment in the lysosome. This study represents the first demonstration of lysosome‐targeted delivery of CO. However, our findings also note the nonuniversal nature for a morpholine moiety to lead to lysosomal enrichment. The modest magnitude of enrichment also means that this method may only be applicable for targeted delivery of a highly potent drug.","journal":"Chemical Biology & Drug Design","year":2025,"id":572522,"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":0.9439,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"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":1068646,"name":"Dongning Liu","orcid":"0009-0008-0505-6851","position":1,"is_corresponding":false},{"id":292035,"name":"Xiaoxiao Yang","orcid":"0000-0001-9895-9559","position":2,"is_corresponding":false},{"id":1263793,"name":"Ce Yang","orcid":"0000-0002-2830-6672","position":3,"is_corresponding":false},{"id":867688,"name":"Lu Wen","orcid":"0000-0003-2203-5119","position":4,"is_corresponding":false},{"id":1203015,"name":"Qiyue Mao","orcid":"0000-0002-2834-5890","position":5,"is_corresponding":false},{"id":292038,"name":"Binghe Wang","orcid":"0000-0002-2200-5270","position":6,"is_corresponding":false},{"id":382478,"name":"Ravi Tripathi","orcid":"0000-0001-9912-3374","position":0,"is_corresponding":true}],"reference_count":41,"raw_metadata":null,"created_at":"2026-07-19T02:57:23.653298Z","pmid":"40817746","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":[]}