{"doi":"10.1021/acsabm.4c01176","title":"Diblock Copolymer Targeted Lipid Nanoparticles: Next-Generation Nucleic Acid Delivery System Produced by Confined Impinging Jet Mixers","abstract":"Despite the recent advances and clinical demonstration of lipid nanoparticles (LNPs) for therapeutic and prophylactic applications, the extrahepatic delivery of nucleic acids remains a significant challenge in the field. This limitation arises from the rapid desorption of lipid-PEG in the bloodstream and clearance to the liver, which hinders extrahepatic delivery. In response, we explore the substitution of lipid-PEG with biodegradable block copolymers (BCPs), specifically poly(ε-caprolactone)- block -poly(ethylene glycol) (PCL- b -PEG). BCPs offer strong anchoring for large macromolecules, potentially enhancing cell-specific targeting. To develop and optimize BCP-stabilized LNPs (BCP-LNPs), we employed a Design of Experiment (DOE) approach. Through a systematic exploration, we identified optimal formulations for BCP-LNPs, achieving desirable physicochemical properties and encapsulation efficiency. Notably, BCP-LNPs exhibit surprising trends in transfection efficiency, with certain formulations showing up to a 40-fold increase in transfection in Hela cells, while maintaining minimal cytotoxicity. The lipid compositions that optimized PCL- b -PEG LNP transfection were different from the compositions that optimized PEG-lipid LNP transfection. Furthermore, our study confirms the versatility of BCP-LNPs in encapsulating and delivering both mRNA and pDNA, demonstrating their cargo-agnostic nature. Lastly, we showcased the targeted BCP-LNPs using a Cetuximab-conjugated formulation. These targeted LNPs show significant promise in delivering cargo specific to EGFR-overexpressing cells (A549 cells), with up to 2.4 times higher transfection compared to nontargeted LNPs. This finding underscores the potential of BCP-LNPs in targeted gene therapy, especially in challenging scenarios such as tumor targeting. Overall, our study establishes the viability of BCP-LNPs as a versatile, efficient, and targeted delivery platform for nucleic acids, opening avenues for advanced therapeutic applications.","journal":"ACS Applied Bio Materials","year":2024,"id":472304,"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":2,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9573,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"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":1307772,"name":"Sai Nikhil Subraveti","orcid":null,"position":1,"is_corresponding":false},{"id":1054068,"name":"Jason Liu","orcid":"0000-0001-9040-9253","position":2,"is_corresponding":false},{"id":1307379,"name":"Satya K. Nayagam","orcid":"0000-0001-7377-6465","position":3,"is_corresponding":false},{"id":1307773,"name":"Safaa Merghoub","orcid":null,"position":4,"is_corresponding":false},{"id":1307380,"name":"Nicholas J. Caggiano","orcid":"0000-0002-2182-6114","position":5,"is_corresponding":false},{"id":1307774,"name":"David F. Amelemah","orcid":null,"position":6,"is_corresponding":false},{"id":1307381,"name":"Ting Jiang","orcid":"0000-0001-6930-5193","position":7,"is_corresponding":false},{"id":1307382,"name":"Navid Bizmark","orcid":"0000-0002-1582-9909","position":8,"is_corresponding":false},{"id":226585,"name":"Jonathan M. Conway","orcid":"0000-0002-2715-2149","position":9,"is_corresponding":false},{"id":329899,"name":"Andrew Tsourkas","orcid":"0000-0001-7758-1753","position":10,"is_corresponding":false},{"id":480890,"name":"Robert K. Prud’homme","orcid":"0000-0003-2858-0097","position":11,"is_corresponding":false},{"id":789068,"name":"Bumjun Kim","orcid":"0000-0002-2198-5342","position":0,"is_corresponding":true}],"reference_count":61,"raw_metadata":null,"created_at":"2026-07-19T02:05:53.032464Z","pmid":"39480746","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":[]}