{"doi":"10.1007/s11095-025-03890-8","title":"Mechanism of pH-sensitive Amphiphilic Endosomal Escape of Ionizable Lipid Nanoparticles for Cytosolic Nucleic Acid Delivery","abstract":"Lipid nanoparticles (LNPs) are among the most successful classes of nonviral delivery systems for nucleic acid-based therapeutics in treating human diseases. One of the key challenges in achieving efficient cytosolic delivery of nucleic acids is overcoming endosomal entrapment within cells. Conventional lipid bilayer-forming cationic and amino lipids mediate endosomal escape via the mechanism of lamellar-to-inverted hexagonal phase transition, resulting in suboptimal cytosolic cargo delivery. pH-sensitive amphiphilic cell membrane disruption and endosomal escape have emerged as a strategy for designing protonatable or ionizable lipids, especially nonlamellar lipids, for efficient cytosolic nucleic acid delivery. Nonlamellar amino lipids possess a large wedge-shaped tail structure and do not form stable lipid bilayers. These lipids and their corresponding LNPs remain neutral, non-amphiphilic, or minimally amphiphilic at physiological pH (7.4). They become amphiphilic upon protonation or ionization in acidic endosomes (pH 6.5-5.4). The electrostatic interaction of ionized nonlamellar lipids with the negatively charged endosome membrane, combined with their large wedge-like structures, disrupts the lipid bilayer, facilitating efficient endosomal escape. Additionally, the nonlamellar ionizable lipids can be fine-tuned by altering the structure of amino head groups and lipid tails to achieve the precisely controlled pH-sensitive amphiphilic membrane disruption at endosomal pH. Therefore, these lipids exhibit excellent safety profiles and high efficiency for in vivo delivery of various therapeutic nucleic acids. pH-sensitive amphiphilic membrane disruption and endosomal escape provide a feasible and effective mechanism for designing ionizable lipids for safe and efficient in vivo nucleic acid delivery.","journal":"Pharmaceutical Research","year":2025,"id":509513,"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":32,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9487,"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":523966,"name":"Da Sun","orcid":"0000-0003-4170-1981","position":1,"is_corresponding":false},{"id":364020,"name":"Zheng‐Rong Lu","orcid":"0000-0001-8185-9519","position":0,"is_corresponding":true}],"reference_count":79,"raw_metadata":null,"created_at":"2026-07-19T02:47:24.513904Z","pmid":"40629129","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":[]}