Strnad, P., McElvaney, N. G. & Lomas, D. A. Alpha1-antitrypsin deficiency. N. Engl. J. Med. 382, 1443–1455 (2020).
Google Scholar
Tejwani, V. & Stoller, J. K. The spectrum of clinical sequelae associated with alpha-1 antitrypsin deficiency. Ther. Adv. Chronic Dis. 12_suppl:2040622321995691 (2021).
Santos, G. F., Ellis, P., Farrugia, D. & Turner, A. M. Nephrotic syndrome secondary to alpha-1 antitrypsin deficiency. BMJ Case Rep. 14, e240288 (2021).
Google Scholar
Loring, H. S. & Flotte, T. R. Current status of gene therapy for α-1 antitrypsin deficiency. Expert Opin. Biol. Ther. 15, 329–336 (2015).
Google Scholar
Hamesch, K. & Strnad, P. Non-invasive assessment and management of liver involvement in adults with alpha-1 antitrypsin deficiency. Chronic Obstr. Pulm. Dis. 7, 260–271 (2020).
Google Scholar
Cazzola, M., Stolz, D., Rogliani, P. & Matera, M. G. α1-Antitrypsin deficiency and chronic respiratory disorders. Eur. Respir. Rev. 29, 190073 (2020).
Google Scholar
Packer, M. S. et al. Evaluation of cytosine base editing and adenine base editing as a potential treatment for alpha-1 antitrypsin deficiency. Mol. Ther. 30, 1396–1406 (2022).
Google Scholar
Werder, R. B. et al. Adenine base editing reduces misfolded protein accumulation and toxicity in alpha-1 antitrypsin deficient patient iPSC-hepatocytes. Mol. Ther. 29, 3219–3229 (2021).
Google Scholar
Stiles, K. M. et al. Intrapleural gene therapy for alpha-1 antitrypsin deficiency-related lung disease. Chronic Obstr. Pulm. Dis. 5, 244–257 (2018).
Google Scholar
Janosz, E. et al. Pulmonary transplantation of alpha-1 antitrypsin (AAT)-transgenic macrophages provides a source of functional human AAT in vivo. Gene Ther. 28, 477–493 (2021).
Google Scholar
Chiuchiolo, M. J. & Crystal, R. G. Gene therapy for alpha-1 antitrypsin deficiency lung disease. Ann. Am. Thorac. Soc. 13, S352–S369 (2016).
Google Scholar
Raevens, S., Boret, M., De Pauw, M., Fallon, M. B. & Van Vlierberghe, H. Pulmonary abnormalities in liver disease: relevance to transplantation and outcome. Hepatology 74, 1674–1686 (2021).
Google Scholar
Zamora, M. R. & Ataya, A. Lung and liver transplantation in patients with alpha-1 antitrypsin deficiency. Ther. Adv. Chronic Dis. 12_suppl:20406223211002988 (2021).
Conrad, A. et al. Impact of alpha 1-antitrypsin deficiency and prior augmentation therapy on patients’ survival after lung transplantation. Eur. Respir. J. 50, 1700962 (2017).
Google Scholar
Gulack, B. C. et al. Survival after lung transplantation in recipients with alpha-1-antitrypsin deficiency compared to other forms of chronic obstructive pulmonary disease: a national cohort study. Transpl. Int. 31, 45–55 (2018).
Google Scholar
van ‘t Wout, E. F., van Schadewijk, A., Savage, N. D., Stolk, J. & Hiemstra, P. S. α1-Antitrypsin production by proinflammatory and antiinflammatory macrophages and dendritic cells. Am. J. Respir. Cell Mol. Biol. 46, 607–613 (2012).
Google Scholar
Belchamber, K. B. R., Walker, E. M., Stockley, R. A. & Sapey, E. Monocytes and macrophages in alpha-1 antitrypsin deficiency. Int. J. Chron. Obstruct. Pulmon. Dis. 15, 3183–3192 (2020).
Google Scholar
Hurley, K. et al. Deriving type II alveolar cells from pluripotent stem cells to produce a novel model of alpha-1 antitrypsin deficiency pathogenesis. Eur. Respir. J. 48, PA4659 (2016).
Pini, L. et al. The role of bronchial epithelial cells in the pathogenesis of COPD in Z-alpha-1 antitrypsin deficiency. Respir. Res. 15, 112 (2014).
Google Scholar
Abo, K. M. et al. Pulmonary cellular toxicity in alpha-1 antitrypsin deficiency. Chest 166, 472–479 (2024).
Google Scholar
Vieira Braga, F. A. et al. A cellular census of human lungs identifies novel cell states in health and in asthma. Nat. Med. 25, 1153–1163 (2019).
Google Scholar
Zhou, K. et al. Modular degradable dendrimers enable small RNAs to extend survival in an aggressive liver cancer model. Proc. Natl Acad. Sci. USA 113, 520–525 (2016).
Google Scholar
Dong, Y., Siegwart, D. J. & Anderson, D. G. Strategies, design, and chemistry in siRNA delivery systems. Adv. Drug Deliv. Rev. 144, 133–147 (2019).
Google Scholar
Han, X. et al. Ligand-tethered lipid nanoparticles for targeted RNA delivery to treat liver fibrosis. Nat. Commun. 14, 75 (2023).
Google Scholar
Cheng, Q. et al. Dendrimer-based lipid nanoparticles deliver therapeutic FAH mRNA to normalize liver function and extend survival in a mouse model of hepatorenal tyrosinemia type I. Adv. Mater. 30, e1805308 (2018).
Google Scholar
Hou, X. et al. Vitamin lipid nanoparticles enable adoptive macrophage transfer for the treatment of multidrug-resistant bacterial sepsis. Nat. Nanotechnol. 15, 41–46 (2020).
Google Scholar
Liu, S. et al. Membrane-destabilizing ionizable phospholipids for organ-selective mRNA delivery and CRISPR–Cas gene editing. Nat. Mater. 20, 701–710 (2021).
Google Scholar
Alvarez-Benedicto, E. et al. Spleen SORT LNP generated in situ CAR T cells extend survival in a mouse model of lymphoreplete B cell lymphoma. Angew. Chem. Int. Ed. Engl. 62, e202310395 (2023).
Google Scholar
Cheng, Q. et al. In situ production and secretion of proteins endow therapeutic benefit against psoriasiform dermatitis and melanoma. Proc. Natl Acad. Sci. USA 120, e2313009120 (2023).
Google Scholar
Han, X. et al. Adjuvant lipidoid-substituted lipid nanoparticles augment the immunogenicity of SARS-CoV-2 mRNA vaccines. Nat. Nanotechnol. 18, 1105–1114 (2023).
Google Scholar
Xue, L. et al. Combinatorial design of siloxane-incorporated lipid nanoparticles augments intracellular processing for tissue-specific mRNA therapeutic delivery. Nat. Nanotechnol. 20, 132–143 (2024).
Gong, N. Q. et al. Tumour-derived small extracellular vesicles act as a barrier to therapeutic nanoparticle delivery. Nat. Mater. 23, 1736–1747 (2024).
Google Scholar
Chaudhary, N. et al. Amine headgroups in ionizable lipids drive immune responses to lipid nanoparticles by binding to the receptors TLR4 and CD1d. Nat. Biomed. Eng. 8, 1483–1498 (2024).
Google Scholar
Petersen, D. M. S. et al. Branched-tail lipid nanoparticles for intravenous mRNA delivery to lung immune, endothelial, and alveolar cells in mice. Adv. Healthc. Mater. 13, e2400225 (2024).
Google Scholar
Mukherjee, A. et al. Engineered mutant α-ENaC subunit mRNA delivered by lipid nanoparticles reduces amiloride currents in cystic fibrosis-based cell and mice models. Sci. Adv. 6, eabc5911 (2020).
Google Scholar
Xu, S. F. et al. Tumor-tailored ionizable lipid nanoparticles facilitate IL-12 circular RNA delivery for enhanced lung cancer immunotherapy. Adv. Mater. 36, e2400307 (2024).
Google Scholar
Li, B. W. et al. Accelerating ionizable lipid discovery for mRNA delivery using machine learning and combinatorial chemistry. Nat. Mater. 23, 1002–1008 (2024).
Google Scholar
Miller, J. B. et al. Non-viral CRISPR/Cas gene editing in vitro and in vivo enabled by synthetic nanoparticle co-delivery of Cas9 mRNA and sgRNA. Angew. Chem. Int. Ed. Engl. 56, 1059–1063 (2017).
Google Scholar
Finn, J. D. et al. A single administration of CRISPR/Cas9 lipid nanoparticles achieves robust and persistent in vivo genome editing. Cell Rep. 22, 2227–2235 (2018).
Google Scholar
Cheng, Q. et al. Selective organ targeting (SORT) nanoparticles for tissue-specific mRNA delivery and CRISPR–Cas gene editing. Nat. Nanotechnol. 15, 313–320 (2020).
Google Scholar
Musunuru, K. et al. In vivo CRISPR base editing of PCSK9 durably lowers cholesterol in primates. Nature 593, 429–434 (2021).
Google Scholar
Tsuchida, C. A., Wasko, K. M., Hamilton, J. R. & Doudna, J. A. Targeted nonviral delivery of genome editors in vivo. Proc. Natl Acad. Sci. USA 121, e2307796121 (2024).
Google Scholar
Ely, Z. A. et al. A prime editor mouse to model a broad spectrum of somatic mutations in vivo. Nat. Biotechnol. 42, 424–436 (2024).
Google Scholar
Jiang, C. et al. A non-viral CRISPR/Cas9 delivery system for therapeutically targeting HBV DNA and pcsk9 in vivo. Cell Res. 27, 440–443 (2017).
Google Scholar
Han, J. P. et al. In vivo delivery of CRISPR–Cas9 using lipid nanoparticles enables antithrombin gene editing for sustainable hemophilia A and B therapy. Sci. Adv. 8, eabj6901 (2022).
Google Scholar
Li, B. et al. Combinatorial design of nanoparticles for pulmonary mRNA delivery and genome editing. Nat. Biotechnol. 41, 1410–1415 (2023).
Google Scholar
Gao, S. L. et al. Harnessing non-Watson–Crick’s base pairing to enhance CRISPR effectors cleavage activities and enable gene editing in mammalian cells. Proc. Natl Acad. Sci. USA 121, e2308415120 (2024).
Google Scholar
Anzalone, A. V., Koblan, L. W. & Liu, D. R. Genome editing with CRISPR–Cas nucleases, base editors, transposases and prime editors. Nat. Biotechnol. 38, 824–844 (2020).
Google Scholar
Song, C. Q. et al. Adenine base editing in an adult mouse model of tyrosinaemia. Nat. Biomed. Eng. 4, 125–130 (2020).
Google Scholar
Rothgangl, T. et al. In vivo adenine base editing of PCSK9 in macaques reduces LDL cholesterol levels. Nat. Biotechnol. 39, 949–957 (2021).
Google Scholar
Ryu, S. M. et al. Adenine base editing in mouse embryos and an adult mouse model of Duchenne muscular dystrophy. Nat. Biotechnol. 36, 536–539 (2018).
Google Scholar
Lee, S. M. et al. A systematic study of unsaturation in lipid nanoparticles leads to improved mRNA transfection in vivo. Angew. Chem. Int. Ed. Engl. 60, 5848–5853 (2021).
Google Scholar
Wang, X. et al. Preparation of selective organ-targeting (SORT) lipid nanoparticles (LNPs) using multiple technical methods for tissue-specific mRNA delivery. Nat. Protoc. 18, 265–291 (2023).
Google Scholar
Wei, T. et al. Lung SORT LNPs enable precise homology-directed repair mediated CRISPR/Cas genome correction in cystic fibrosis models. Nat. Commun. 14, 7322 (2023).
Google Scholar
Shepherd, S. J., Issadore, D. & Mitchell, M. J. Microfluidic formulation of nanoparticles for biomedical applications. Biomaterials 274, 120826 (2021).
Google Scholar
van ‘t Wou, E. F. et al. Increased ERK signalling promotes inflammatory signalling in primary airway epithelial cells expressing Z α1-antitrypsin. Hum. Mol. Genet. 23, 929–941 (2014).
Google Scholar
Richter, M. F. et al. Phage-assisted evolution of an adenine base editor with improved Cas domain compatibility and activity. Nat. Biotechnol. 38, 883–891 (2020).
Google Scholar
Abbasi, S. et al. Co-encapsulation of Cas9 mRNA and guide RNA in polyplex micelles enables genome editing in mouse brain. J. Control. Release 332, 260–268 (2021).
Google Scholar
Schmidheini, L. et al. Continuous directed evolution of a compact CjCas9 variant with broad PAM compatibility. Nat. Chem. Biol. 20, 333–343 (2024).
Google Scholar
Hoseini, B. et al. Application of ensemble machine learning approach to assess the factors affecting size and polydispersity index of liposomal nanoparticles. Sci. Rep. 13, 18012 (2023).
Google Scholar
Danaei, M. et al. Impact of particle size and polydispersity index on the clinical applications of lipidic nanocarrier systems. Pharmaceutics 10, 57 (2018).
Google Scholar
North, T. L. et al. A study of common Mendelian disease carriers across ageing British cohorts: meta-analyses reveal heterozygosity for alpha 1-antitrypsin deficiency increases respiratory capacity and height. J. Med. Genet. 53, 280–288 (2016).
Google Scholar
Shen, S. et al. Amelioration of alpha-1 antitrypsin deficiency diseases with genome editing in transgenic mice. Hum. Gene Ther. 29, 861–873 (2018).
Google Scholar
Carlson, J. A. et al. Accumulation of PiZ alpha 1-antitrypsin causes liver damage in transgenic mice. J. Clin. Invest. 83, 1183–1190 (1989).
Google Scholar
Bjursell, M. et al. Therapeutic genome editing with CRISPR/Cas9 in a humanized mouse model ameliorates α1-antitrypsin deficiency phenotype. EBioMedicine 29, 104–111 (2018).
Google Scholar
Mitchell, E. L. & Khan, Z. Liver disease in alpha-1 antitrypsin deficiency: current approaches and future directions. Curr. Pathobiol. Rep. 5, 243–252 (2017).
Google Scholar
Santos, G. & Turner, A. M. Alpha-1 antitrypsin deficiency: an update on clinical aspects of diagnosis and management. Fac. Rev. 9, 1 (2020).
Google Scholar
Piccolo, P. et al. Down-regulation of hepatocyte nuclear factor-4α and defective zonation in livers expressing mutant Z α1-antitrypsin. Hepatology 66, 124–135 (2017).
Google Scholar
Mela, M. et al. The alpha-1 antitrypsin polymer load correlates with hepatocyte senescence, fibrosis stage and liver-related mortality. Chronic Obstr. Pulm. Dis. 7, 151–162 (2020).
Google Scholar
Strnad, P. et al. Fazirsiran for liver disease associated with alpha1-antitrypsin deficiency. N. Engl. J. Med. 387, 514–524 (2022).
Google Scholar
Zorzetto, M. et al. SERPINA1 gene variants in individuals from the general population with reduced α1-antitrypsin concentrations. Clin. Chem. 54, 1331–1338 (2008).
Google Scholar
Chen, K. et al. Lung and liver editing by lipid nanoparticle delivery of a stable CRISPR–Cas9 ribonucleoprotein. Nat. Biotechnol. https://doi.org/10.1038/s41587-024-02437-3 (2024).
Xue, L. et al. Combinatorial design of siloxane-incorporated lipid nanoparticles augments intracellular processing for tissue-specific mRNA therapeutic delivery. Nat. Nanotechnol. 20, 132–143 (2025).
Google Scholar
Karadagi, A. et al. Systemic modified messenger RNA for replacement therapy in alpha 1-antitrypsin deficiency. Sci. Rep. 10, 7052 (2020).
Google Scholar
Dilliard, S. A. et al. The interplay of quaternary ammonium lipid structure and protein corona on lung-specific mRNA delivery by selective organ targeting (SORT) nanoparticles. J. Control. Release 361, 361–372 (2023).
Google Scholar
Takahashi, Y., Nishikawa, M., Takiguchi, N., Suehara, T. & Takakura, Y. Saturation of transgene protein synthesis from mRNA in cells producing a large number of transgene mRNA. Biotechnol. Bioeng. 108, 2380–2389 (2011).
Google Scholar
Ogushi, F., Fells, G. A., Hubbard, R. C., Straus, S. D. & Crystal, R. G. Z-type alpha 1-antitrypsin is less competent than M1-type alpha 1-antitrypsin as an inhibitor of neutrophil elastase. J. Clin. Invest. 80, 1366–1374 (1987).
Google Scholar
Molloy, K. et al. Clarification of the risk of chronic obstructive pulmonary disease in α1-antitrypsin deficiency PiMZ heterozygotes. Am. J. Respir. Crit. Care Med. 189, 419–427 (2014).
Google Scholar
Sorheim, I. C. et al. α1-Antitrypsin protease inhibitor MZ heterozygosity is associated with airflow obstruction in two large cohorts. Chest 138, 1125–1132 (2010).
Google Scholar
Piloni, D. et al. Comparison among populations with severe and intermediate alpha1-antitrypsin deficiency and chronic obstructive pulmonary disease. Minerva Med. 115, 23–31 (2024).
Google Scholar
Raguram, A., Banskota, S. & Liu, D. R. Therapeutic in vivo delivery of gene editing agents. Cell 185, 2806–2827 (2022).
Google Scholar
He, N. et al. Ferret models of alpha-1 antitrypsin deficiency develop lung and liver disease. JCI Insight 7, e143004 (2022).
Google Scholar
Mandal, P. K. & Rossi, D. J. Reprogramming human fibroblasts to pluripotency using modified mRNA. Nat. Protoc. 8, 568–582 (2013).
Google Scholar
Ryan, D. E. et al. Phosphonoacetate modifications enhance the stability and editing yields of guide RNAs for Cas9 editors. Biochemistry 62, 3512–3520 (2023).
Google Scholar
Choi, J. et al. Inflammatory signals induce AT2 cell-derived damage-associated transient progenitors that mediate alveolar regeneration. Cell Stem Cell 27, 366–382 (2020).
Google Scholar
Hasegawa, K. et al. Fraction of MHCII and EpCAM expression characterizes distal lung epithelial cells for alveolar type 2 cell isolation. Respir. Res. 18, 150 (2017).
Google Scholar
Bae, S., Park, J. & Kim, J. S. Cas-OFFinder: a fast and versatile algorithm that searches for potential off-target sites of Cas9 RNA-guided endonucleases. Bioinformatics 30, 1473–1475 (2014).
Google Scholar
Clement, K. et al. CRISPResso2 provides accurate and rapid genome editing sequence analysis. Nat. Biotechnol. 37, 224–226 (2019).
Google Scholar
Muller, T. & Winter, D. Systematic evaluation of protein reduction and alkylation reveals massive unspecific side effects by iodine-containing reagents. Mol. Cell Proteomics. 16, 1173–1187 (2017).
Google Scholar
Gundry, R. L. et al. Preparation of proteins and peptides for mass spectrometry analysis in a bottom-up proteomics workflow. Curr. Protoc. Mol. Biol. Chapter 10, Unit10.25 (2009).
