{"doi":"10.1016/j.mattod.2025.11.032","title":"Biodegradable lipid nanoparticles for genome editing in the brain via intrathecal administration","abstract":"Messenger RNA (mRNA)-based nonviral delivery of gene editors offers transformative potential for therapeutic genome editing in neurological diseases, but efficient and safe delivery to the brain remains a formidable challenge due to the restrictive blood–brain barrier. Intrathecal administration provides a clinically validated route to bypass this barrier, yet the design principles for biodegradable lipid nanoparticles (LNPs) optimized for central nervous system (CNS) delivery remain poorly defined. Here, we synthesized a 200-member combinatorial library of structurally diverse, biodegradable ionizable lipids using the Passerini three-component reaction. High-throughput in vivo screening identified P3B, a lead lipid incorporating degradable linkages and optimized ionizable head groups, which enables potent and well-tolerated intrathecal mRNA delivery. In Ai9 reporter mice, P3B-LNPs encapsulating Cas9 mRNA/sgRNA induced robust and widespread tdTomato expression in neurons and astrocytes across multiple brain regions, achieving substantially higher editing efficiency than the clinical benchmark DLin-MC3-DMA (MC3). In LumA reporter mice, P3B-LNPs mediated efficient adenine base editing, restoring luciferase expression throughout the brain with 14.8% on-target correction and minimal off-target activity. Compared with MC3, P3B-LNPs exhibited enhanced tolerability, with attenuated inflammatory responses and a safety profile supportive of repeated dosing. These findings establish P3B-LNPs as a potent, safe, and biodegradable platform for genome editing in the brain and underscore the power of combinatorial lipid chemistry and high-throughput in vivo screening to accelerate the development of next-generation LNPs for CNS-targeted mRNA therapeutics.","journal":"Materials Today","year":2025,"id":527688,"datarank":0.20794415416798362,"base_score":1.3862943611198906,"endowment":1.3862943611198906,"self_citation_contribution":0.20794415416798362,"citation_network_contribution":0.0,"self_endowment_contribution":0.20794415416798362,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":3,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9498,"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":1405042,"name":"Lauren Healy","orcid":"0009-0003-5772-3269","position":1,"is_corresponding":false},{"id":1405579,"name":"Fanglin Gong","orcid":null,"position":2,"is_corresponding":false},{"id":1405043,"name":"Yue Xu","orcid":"0009-0006-2151-4694","position":3,"is_corresponding":false},{"id":1405580,"name":"Yunshu Cai","orcid":null,"position":4,"is_corresponding":false},{"id":1405044,"name":"Nicholas C. Solek","orcid":"0009-0008-6336-0229","position":5,"is_corresponding":false},{"id":1164658,"name":"Jingan Chen","orcid":null,"position":6,"is_corresponding":false},{"id":1405581,"name":"Muye Zhou","orcid":null,"position":7,"is_corresponding":false},{"id":1405045,"name":"Tyler Thomson","orcid":"0000-0002-1434-1813","position":8,"is_corresponding":false},{"id":1405582,"name":"Margarita Savguira","orcid":null,"position":9,"is_corresponding":false},{"id":848035,"name":"Sijin Luozhong","orcid":"0000-0001-8697-9480","position":10,"is_corresponding":false},{"id":1405046,"name":"Yanchao Zhang","orcid":"0000-0001-7671-725X","position":11,"is_corresponding":false},{"id":1405583,"name":"Tingzhen He","orcid":null,"position":12,"is_corresponding":false},{"id":1405047,"name":"Gen Li","orcid":"0000-0002-0644-5989","position":13,"is_corresponding":false},{"id":307084,"name":"Bowen Li","orcid":"0000-0001-5006-9143","position":14,"is_corresponding":false},{"id":1405041,"name":"Songtao Dong","orcid":"0000-0002-0030-0842","position":0,"is_corresponding":true}],"reference_count":56,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T02:50:44.062153Z","pmid":"42388231","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":[]}