{"doi":"10.1021/jacs.4c10265","title":"Multiarm-Assisted Design of Dendron-like Degradable Ionizable Lipids Facilitates Systemic mRNA Delivery to the Spleen","abstract":"Lipid nanoparticles (LNPs) have emerged as pivotal vehicles for messenger RNA (mRNA) delivery to hepatocytes upon systemic administration and to antigen-presenting cells following intramuscular injection. However, achieving systemic mRNA delivery to non-hepatocytes remains challenging without the incorporation of targeting ligands such as antibodies, peptides, or small molecules. Inspired by comb-like polymeric architecture, here we utilized a multiarm-assisted design to construct a library of 270 dendron-like degradable ionizable lipids by altering the structures of amine heads and multiarmed tails for optimal mRNA delivery. Following in vitro high-throughput screening, a series of top-dendron-like LNPs with high transfection efficacy were identified. These dendron-like ionizable lipids facilitated greater mRNA delivery to the spleen in vivo compared to ionizable lipid analogs lacking dendron-like structure. Proteomic analysis of corona-LNP pellets showed enhancement of key protein clusters, suggesting potential endogenous targeting to the spleen. A lead dendron-like LNP formulation, 18-2-9b2, was further used to encapsulate Cre mRNA and demonstrated excellent genome modification in splenic macrophages, outperforming a spleen-tropic MC3/18PA LNP in the Ai14 mice model. Moreover, 18-2-9b2 LNP encapsulating therapeutic BTB domain and CNC homologue 1 (BACH1) mRNA exhibited proficient BACH1 expression and subsequent Spic downregulation in splenic red pulp macrophages (RPM) in a Spic-GFP transgene model upon intravenous administration. These results underscore the potential of dendron-like LNPs to facilitate mRNA delivery to splenic macrophages, potentially opening avenues for a range of mRNA-LNP therapeutic applications, including regenerative medicine, protein replacement, and gene editing therapies.","journal":"Journal of the American Chemical Society","year":2025,"id":509403,"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":34,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9496,"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":844962,"name":"Xinhong Xiong","orcid":null,"position":1,"is_corresponding":false},{"id":324332,"name":"Gan Zhao","orcid":"0000-0002-8043-6036","position":2,"is_corresponding":false},{"id":911333,"name":"William A. Molina Arocho","orcid":"0000-0002-5864-1383","position":3,"is_corresponding":false},{"id":1008366,"name":"Rohan Palanki","orcid":"0000-0001-5168-5634","position":4,"is_corresponding":false},{"id":486934,"name":"Zebin Xiao","orcid":"0000-0002-3311-7403","position":5,"is_corresponding":false},{"id":615519,"name":"Xuexiang Han","orcid":"0000-0003-0011-5222","position":6,"is_corresponding":false},{"id":1202114,"name":"Il‐Chul Yoon","orcid":null,"position":7,"is_corresponding":false},{"id":317803,"name":"Christian G. Figueroa‐Espada","orcid":"0000-0003-2700-7678","position":8,"is_corresponding":false},{"id":1014874,"name":"Junchao Xu","orcid":"0000-0003-0725-8111","position":9,"is_corresponding":false},{"id":240732,"name":"Ningqiang Gong","orcid":"0000-0002-9444-8505","position":10,"is_corresponding":false},{"id":1215593,"name":"Qiangqiang Shi","orcid":"0009-0005-8439-1807","position":11,"is_corresponding":false},{"id":1216291,"name":"Qinyuan Chen","orcid":null,"position":12,"is_corresponding":false},{"id":231967,"name":"Mohamad‐Gabriel Alameh","orcid":"0000-0002-5672-6930","position":13,"is_corresponding":false},{"id":324336,"name":"Andrew E. Vaughan","orcid":"0000-0001-5740-643X","position":14,"is_corresponding":false},{"id":29530,"name":"Malay Haldar","orcid":"0000-0003-3776-0516","position":15,"is_corresponding":false},{"id":246178,"name":"Karin Wang","orcid":"0000-0001-7812-2583","position":16,"is_corresponding":false},{"id":20753,"name":"Drew Weissman","orcid":"0000-0002-1501-6510","position":17,"is_corresponding":false},{"id":103470,"name":"Michael J. Mitchell","orcid":"0000-0002-3628-2244","position":18,"is_corresponding":false},{"id":843715,"name":"Lulu Xue","orcid":"0000-0001-5719-1336","position":0,"is_corresponding":true}],"reference_count":65,"raw_metadata":null,"created_at":"2026-07-19T02:47:24.513904Z","pmid":"39742515","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":[]}