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A highly mobile adeno-associated virus targeting vascular smooth muscle cells for the treatment of pulmonary arterial hypertension

Nature Biomedical Engineering volume 9, pages 1418–1436 (2025)Cite this article

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Abstract

In pulmonary arterial hypertension (PAH), a phenotypic switch in pulmonary arterial smooth muscle cells (PASMCs) that is primarily caused by aberrant gene regulatory networks can lead to dysregulated vascular remodelling, heart failure or death. No curative therapies for PAH are currently available, presumably because of a lack of viral vectors specifically targeting PASMCs. Here we show that a highly mobile and PASMC-tropic adeno-associated virus variant developed via directed evolution overcomes physical barriers that inhibit its transfer from bronchial airways to vascular layers, ultimately boosting therapeutic efficacy in murine models of PAH. Intratracheal administration of the adeno-associated virus variant carrying a transgene for fibroblast growth factor 12—a key factor regulating the PASMC phenotype—suppressed pulmonary vascular remodelling, prevented the development of PAH in mice and reversed established PAH in rats. The variant’s mobility and enhanced tropism for PASMCs may enable curative treatments for PAH.

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Fig. 1: Enhanced PASMC-tropic characteristics of AAVp2CV.
Fig. 2: Enhanced diffusion of AAVp2CV across pulmonary tissues.
Fig. 3: Reduced off-targets of AAVp2CV.
Fig. 4: Roles of point mutations in AAVp2CV.
Fig. 5: Analysis of the diffusive properties of AAVp2CV.
Fig. 6: Characterization of AAVp2CV as a gene delivery vehicle.
Fig. 7: Prevention of PAH in mice by intratracheal injection of AAVp2CV-FGF12.
Fig. 8: Therapeutic reversal of established PAH in rats by intratracheal injection of AAVp2CV-FGF12.

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Data availability

The data supporting the results in this study are available within the paper and its Supplementary Information. Source data are provided with this paper.

References

  1. Farber, H. W. & Loscalzo, J. Pulmonary arterial hypertension. N. Engl. J. Med. 351, 1655–1665 (2004).

    Article  CAS  PubMed  Google Scholar 

  2. Schermuly, R. T., Ghofrani, H. A., Wilkins, M. R. & Grimminger, F. Mechanisms of disease: pulmonary arterial hypertension. Nat. Rev. Cardiol. 8, 443–455 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Thompson, A. R. & Lawrie, A. Targeting vascular remodeling to treat pulmonary arterial hypertension. Trends Mol. Med. 23, 31–45 (2017).

    Article  CAS  PubMed  Google Scholar 

  4. Morrell, N. W. et al. Altered growth responses of pulmonary artery smooth muscle cells from patients with primary pulmonary hypertension to transforming growth factor-β1 and bone morphogenetic proteins. Circulation 104, 790–795 (2001).

    Article  CAS  PubMed  Google Scholar 

  5. Dorai, H., Vukicevic, S. & Sampath, T. K. Bone morphogenetic protein-7 (osteogenic protein-1) inhibits smooth muscle cell proliferation and stimulates the expression of markers that are characteristic of SMC phenotype in vitro. J. Cell. Physiol. 184, 37–45 (2000).

    Article  CAS  PubMed  Google Scholar 

  6. Lagna, G. et al. Control of phenotypic plasticity of smooth muscle cells by bone morphogenetic protein signaling through the myocardin-related transcription factors. J. Biol. Chem. 282, 37244–37255 (2007).

    Article  CAS  PubMed  Google Scholar 

  7. Hu, L. et al. An emerging strategy for targeted therapy of pulmonary arterial hypertension: vasodilation plus vascular remodeling inhibition. Drug Discov. Today 27, 1457–1463 (2022).

    Article  CAS  PubMed  Google Scholar 

  8. Sung, Y. K., Yuan, K. & de Jesus Perez, V. A. Novel approaches to pulmonary arterial hypertension drug discovery. Expert Opin. Drug Discov. 11, 407–414 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Pullamsetti, S. S., Mamazhakypov, A., Weissmann, N., Seeger, W. & Savai, R. Hypoxia-inducible factor signaling in pulmonary hypertension. J. Clin. Invest. 130, 5638–5651 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Yeo, Y. et al. FGF12 (fibroblast growth factor 12) inhibits vascular smooth muscle cell remodeling in pulmonary arterial hypertension. Hypertension 76, 1778–1786 (2020).

    Article  CAS  PubMed  Google Scholar 

  11. Harper, R. L., Reynolds, A. M., Bonder, C. S. & Reynolds, P. N. BMPR2 gene therapy for PAH acts via Smad and non-Smad signalling. Respirology 21, 727–733 (2016).

    Article  PubMed  Google Scholar 

  12. Pousada, G. et al. Molecular and functional characterization of the BMPR2 gene in pulmonary arterial hypertension. Sci. Rep. 7, 1923 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  13. Austin, E. D. & Loyd, J. E. The genetics of pulmonary arterial hypertension. Circ. Res. 115, 189–202 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Hadri, L. et al. Therapeutic efficacy of AAV1.SERCA2a in monocrotaline-induced pulmonary arterial hypertension. Circulation 128, 512–523 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Strauss, B. et al. Intra-tracheal gene delivery of aerosolized SERCA2a to the lung suppresses ventricular arrhythmias in a model of pulmonary arterial hypertension. J. Mol. Cell. Cardiol. 127, 20–30 (2019).

    Article  CAS  PubMed  Google Scholar 

  16. Song, S.-H. et al. Fibroblast growth factor 12 is a novel regulator of vascular smooth muscle cell plasticity and fate. Arterioscler. Thromb. Vasc. Biol. 36, 1928–1936 (2016).

    Article  CAS  PubMed  Google Scholar 

  17. Somlyo, A. P. & Somlyo, A. V. Signal transduction and regulation in smooth muscle. Nature 372, 231–236 (1994).

    Article  CAS  PubMed  Google Scholar 

  18. Pickles, R. J. Physical and biological barriers to viral vector–mediated delivery of genes to the airway epithelium. Proc. Am. Thorac. Soc. 1, 302–308 (2004).

    Article  CAS  PubMed  Google Scholar 

  19. Halbert, C. L. et al. Expression of human α1-antitrypsin in mice and dogs following AAV6 vector-mediated gene transfer to the lungs. Mol. Ther. 18, 1165–1172 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Li, W., Zhang, L., Wu, Z., Pickles, R. J. & Samulski, R. J. AAV-6 mediated efficient transduction of mouse lower airways. Virology 417, 327–333 (2011).

    Article  CAS  PubMed  Google Scholar 

  21. Travaglini, K. J. et al. A molecular cell atlas of the human lung from single-cell RNA sequencing. Nature 587, 619–625 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Braciale, T. J., Sun, J. & Kim, T. S. Regulating the adaptive immune response to respiratory virus infection. Nat. Rev. Immunol. 12, 295–305 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Kucharz, K. et al. Post-capillary venules are the key locus for transcytosis-mediated brain delivery of therapeutic nanoparticles. Nat. Commun. 12, 4121 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Kim, Y. C. et al. Gelling hypotonic polymer solution for extended topical drug delivery to the eye. Nat. Biomed. Eng. 4, 1053–1062 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Yu, M. et al. Rapid transport of deformation-tuned nanoparticles across biological hydrogels and cellular barriers. Nat. Commun. 9, 2607 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  26. Wu, Z., Miller, E., Agbandje-McKenna, M. & Samulski, R. J. α2,3 and α2,6 N-linked sialic acids facilitate efficient binding and transduction by adeno-associated virus types 1 and 6. J. Virol. 80, 9093–9103 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Shirk, R. A., Church, F. C. & Wagner, W. D. Arterial smooth muscle cell heparan sulfate proteoglycans accelerate thrombin inhibition by heparin cofactor II. Arterioscler. Thromb. Vasc. Biol. 16, 1138–1146 (1996).

    Article  CAS  PubMed  Google Scholar 

  28. Aguero, J. et al. Intratracheal gene delivery of SERCA2a ameliorates chronic post-capillary pulmonary hypertension: a large animal model. J. Am. Coll. Cardiol. 67, 2032–2046 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Kotterman, M. A. & Schaffer, D. V. Engineering adeno-associated viruses for clinical gene therapy. Nat. Rev. Genet. 15, 445–451 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Wang, D., Tai, P. W. L. & Gao, G. Adeno-associated virus vector as a platform for gene therapy delivery. Nat. Rev. Drug Discov. 18, 358–378 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Li, C. & Samulski, R. J. Engineering adeno-associated virus vectors for gene therapy. Nat. Rev. Genet. 21, 255–272 (2020).

    Article  CAS  PubMed  Google Scholar 

  32. Carpentier, A. C. et al. Effect of alipogene tiparvovec (AAV1-LPLS447X) on postprandial chylomicron metabolism in lipoprotein lipase-deficient patients. J. Clin. Endocrinol. 97, 1635–1644 (2012).

    Article  CAS  Google Scholar 

  33. Maguire, A. M. et al. Safety and efficacy of gene transfer for Leber’s congenital amaurosis. N. Engl. J. Med. 358, 2240–2248 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. George, L. A. et al. Hemophilia B gene therapy with a high-specific-activity factor IX variant. N. Engl. J. Med. 377, 2215–2227 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Mendell, J. R. et al. Single-dose gene-replacement therapy for spinal muscular atrophy. N. Engl. J. Med. 377, 1713–1722 (2017).

    Article  CAS  PubMed  Google Scholar 

  36. Bisserier, M. et al. Regulation of the methylation and expression levels of the BMPR2 gene by SIN3a as a novel therapeutic mechanism in pulmonary arterial hypertension. Circulation 144, 52–73 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Claude, C. et al. Inhalable delivery of AAV-based MRP4/ABCC4 silencing RNA prevents monocrotaline-induced pulmonary hypertension. Mol. Ther. Methods Clin. Dev. 2, 14065 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  38. Jiang, H. et al. Proteomic analysis reveals that Xbp1s promotes hypoxic pulmonary hypertension through the p-JNK MAPK pathway. J. Cell. Physiol. 237, 1948–1963 (2022).

    Article  CAS  PubMed  Google Scholar 

  39. Duncan, G. A. et al. An adeno-associated viral vector capable of penetrating the mucus barrier to inhaled gene therapy. Mol. Ther. Methods Clin. Dev. 9, 296–304 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Fernandes, D. J., McConville, J. F., Stewart, A. G., Kalinichenko, V. & Solway, J. Can we differentiate between airway and vascular smooth muscle? Clin. Exp. Pharmacol. Physiol. 31, 805–810 (2004).

    Article  CAS  PubMed  Google Scholar 

  41. Moiseenko, A. et al. Origin and characterization of alpha smooth muscle actin-positive cells during murine lung development. Stem Cells 35, 1566–1578 (2017).

    Article  CAS  PubMed  Google Scholar 

  42. Abe, K. et al. Haemodynamic unloading reverses occlusive vascular lesions in severe pulmonary hypertension. Cardiovasc. Res. 111, 16–25 (2016).

    Article  CAS  PubMed  Google Scholar 

  43. Dalkara, D. et al. In vivo-directed evolution of a new adeno-associated virus for therapeutic outer retinal gene delivery from the vitreous. Sci. Transl. Med. 5, 189ra176 (2013).

    Article  Google Scholar 

  44. Jobe, A. H. et al. Surfactant enhances adenovirus-mediated gene expression in rabbit lungs. Gene Ther. 3, 775–779 (1996).

    CAS  PubMed  Google Scholar 

  45. Weiss, D. J. et al. Transient increase in lung epithelial tight junction permeability: an additional mechanism for enhancement of lung transgene expression by perfluorochemical liquids. Mol. Ther. 8, 927–935 (2003).

    Article  CAS  PubMed  Google Scholar 

  46. Asbury, G. R. & Hill, H. H. Jr Separation of amino acids by ion mobility spectrometry. J. Chromatogr. A 902, 433–437 (2000).

    Article  CAS  PubMed  Google Scholar 

  47. Schuster, B. S. et al. Overcoming the cystic fibrosis sputum barrier to leading adeno-associated virus gene therapy vectors. Mol. Ther. 22, 1484–1493 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Huang, L.-Y. et al. Characterization of the adeno-associated virus 1 and 6 sialic acid binding site. J. Virol. 90, 5219–5230 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Wu, Z. et al. Single amino acid changes can influence titer, heparin binding, and tissue tropism in different adeno-associated virus serotypes. J. Virol. 80, 11393–11397 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Nelson, D. & Cox, M. Principles of Biochemistry 4th edn (W.H. Freeman, 2005).

  51. Venkatakrishnan, B. et al. Structure and dynamics of adeno-associated virus serotype 1 VP1-unique N-terminal domain and its role in capsid trafficking. J. Virol. 87, 4974–4984 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Kozlowski, L. P. IPC—Isoelectric Point Calculator. Biol. Direct 11, 55 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  53. Chockalingam, K., Blenner, M. & Banta, S. Design and application of stimulus-responsive peptide systems. Protein Eng. Des. Sel. 20, 155–161 (2007).

    Article  CAS  PubMed  Google Scholar 

  54. Yu, M. et al. The investigation of protein diffusion via H-cell microfluidics. Biophys. J. 116, 595–609 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Johnson, F. B., Ozer, H. L. & Hoggan, M. D. Structural proteins of adenovirus-associated virus type 3. J. Virol. 8, 860–863 (1971).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Rose, J. A. et al. Structural proteins of adenovirus-associated viruses. J. Virol. 8, 766–770 (1971).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Heck, A. et al. Adeno-associated virus capsid assembly is divergent and stochastic. Nat. Commun. 12, 1642 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  58. Koerber, J. T., Maheshri, N., Kaspar, B. K. & Schaffer, D. V. Construction of diverse adeno-associated viral libraries for directed evolution of enhanced gene delivery vehicles. Nat. Protoc. 1, 701–706 (2006).

    Article  CAS  PubMed  Google Scholar 

  59. Jang, J. H. et al. An evolved adeno-associated viral variant enhances gene delivery and gene targeting in neural stem cells. Mol. Ther. 19, 667–675 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Cho, M. et al. Safety and efficacy evaluations of an adeno-associated virus variant for preparing IL10-secreting human neural stem cell-based therapeutics. Gene Ther. 26, 135–150 (2019).

    Article  CAS  PubMed  Google Scholar 

  61. Kang, M. H. et al. A lung tropic AAV vector improves survival in a mouse model of surfactant B deficiency. Nat. Commun. 11, 3929 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Boumahdi, S. et al. SOX2 controls tumour initiation and cancer stem-cell functions in squamous-cell carcinoma. Nature 511, 246–250 (2014).

    Article  CAS  PubMed  Google Scholar 

  63. Lin, H.-T. et al. Application of droplet digital PCR for estimating vector copy number states in stem cell gene therapy. Hum. Gene Ther. Methods 27, 197–208 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Bienkowska-Haba, M. et al. Human papillomavirus genome copy number is maintained by S-phase amplification, genome loss to the cytosol during mitosis, and degradation in G1 phase. J. Virol. 97, e01879–22 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  65. Del Gaudio, D. et al. Increased MECP2 gene copy number as the result of genomic duplication in neurodevelopmentally delayed males. Genet. Med. 8, 784–792 (2006).

    Article  PubMed  Google Scholar 

  66. Filipe, V., Hawe, A. & Jiskoot, W. Critical evaluation of nanoparticle tracking analysis (NTA) by NanoSight for the measurement of nanoparticles and protein aggregates. Pharm. Res. 27, 796–810 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Park, J.-B. et al. Assessment of inflammation in pulmonary artery hypertension by 68Ga-mannosylated human serum albumin. Am. J. Respir. Crit. Care Med. 201, 95–106 (2020).

    Article  CAS  PubMed  Google Scholar 

  68. Brittain, E. et al. Echocardiographic assessment of the right heart in mice. J. Vis. Exp. 81, e50912 (2013).

    Google Scholar 

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Acknowledgements

This research was supported by the National Research Foundation funded by the Ministry of Science and ICT (NRF-2018M3A9H2019045, NRF-2019M3A9H1032791, RS-2023-00219962, RS-2024-00438808 and RS-2024-00451880) and the National Institute of Food and Drug Safety Evaluation (21173MFDS562). This work was also supported by Samsung Research Funding and Incubation Center of Samsung Electronics under project number SRFC-MA2202-08; Korea Drug Development Fund funded by Ministry of Science and ICT, Ministry of Trade, Industry and Energy, and Ministry of Health and Welfare (RS-2023-00217737, Republic of Korea); and a grant of the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (grant number: RS-2024-00438444). Yoojin Kim gratefully acknowledges support from the Basic Science Research Program (NRF-2020R1A6A3A01100408) and the Sejong Science Fellowship (RS-2024-00395068) supported by the National Research Foundation funded by the Korean government (Ministry of Science and ICT). We would like to thank H. Kang, Y. S. Cho and D.-H. Yeom for their help in animal experiments and O. M. Kwon and N. R. Park for their help in animal echocardiography.

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  1. These authors contributed equally: Yoojin Kim, Yeongju Yeo.

Authors and Affiliations

  1. Department of Chemical and Biomolecular Engineering, Yonsei University, Seoul, Korea

    Yoojin Kim, Yong-Wook Son, Joowon Kim, Seohee Kim, Seokmin Oh, Yunha Kim, Hyowoo Lee, Hyun-Woo Park, Dongsoo Lee & Jae-Hyung Jang

  2. Nano Science Technology Institute, Yonsei University, Seoul, Korea

    Yoojin Kim

  3. Department of Global Innovative Drug, the Graduate School of Chung-Ang University, Chung-Ang University, Seoul, Korea

    Yeongju Yeo, Minju Kim & Wonhee Suh

  4. College of Pharmacy, Chung-Ang University, Seoul, Korea

    Yeongju Yeo, Minju Kim, Koung Li Kim & Wonhee Suh

  5. R&D Center, GluGene Therapeutics Inc., Seoul, Korea

    Sung Jin Lee, Changmin Kang, Hongyoung Choi & Jae-Hyung Jang

  6. Division of Cardiology, Department of Internal Medicine, Seoul National University Hospital, Seoul, Korea

    Chan Soon Park & Seung-Pyo Lee

  7. Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea

    Seung-Pyo Lee

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Contributions

W.S. and J.-H.J. conceived and supervised the experiments. Yoojin Kim and Y.Y. performed the majority of the experiments and M.K., Y.-W.S., J.K., S.K., K.L.K., S.O., H.L., H.-W.P., Yunha Kim, D.L. and S.J.L. contributed to the experiments. Yoojin Kim and S.O. constructed the AAV library pool. Yoojin Kim, Y.Y., S.K. and S.O. contributed to the AAVp2CV in vivo selection, including AAV packaging and AAV variants evaluation. Yoojin Kim, Y.Y., Yunha Kim and D.L. conducted the intratracheal surgeries. Yoojin Kim, Y.Y. and K.L.K. assessed the AAV off-targeting by genome quantification and observation of transgene expression. Yoojin Kim and J.K. performed the immunohistochemistry. Yoojin Kim and J.-H.J. performed the AAV trajectory analysis. Y.Y., Yoojin Kim, K.L.K., Yunha Kim, D.L. and M.K. contributed to the preparation of PAH disease models. Y.Y., M.K. and W.S. conducted the haemodynamic assay and Fulton’s index analysis of the PAH models. C.K. and H.C. contributed to the analysis of data obtained from the AAV selection procedure. C.S.P. and S.-P.L. contributed to the echocardiography measurement and interpretation. Yoojin Kim, Y.Y., W.S. and J.-H.J. wrote the paper.

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Correspondence to Wonhee Suh or Jae-Hyung Jang.

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Extended data

Extended Data Fig. 1 In vitro transduction efficiency.

(a) Transduction efficiencies (GFP %) obtained by the four vectors for HEK293T cells (MOI 1 × 104) and HUVECs (MOI 5 × 104) cultured on tissue culture plates (48 h post-infection). AAV2 vector was used as a positive control. (b) GFP intensity obtained by the two vectors in HUVECs (MOI 5 × 104).

Source data

Extended Data Fig. 2 AAVp2CV-FGF12 gene transfer enhances the phosphorylation of MEF2a and the expression of its downstream target genes in PAH mice.

Mice received an intratracheal injection of either saline or AAV and were exposed to chronic hypoxia and weekly injection of SU5416 (Hyp+ SU) for 3 weeks for PAH induction. Mice maintained under normoxia served as the normal control. (a) Protein levels of p-MEF2a, MEF2a, and FGF12 in lung tissues as determined by western blot analysis. The band intensities of p-MEF2a were normalized to those of MEF2a and expressed relative to those of the normal controls (n = 4 biological replicates). (b) mRNA levels of MEF2a target genes related to the cell cycle (Ccne1, Mcm6) and contractile SMC markers (Lmod1, Myocd) as evaluated by real-time RT‒PCR (n = 3–4 biological replicates). All data are presented as the mean ± SEM. (one-way ANOVA with Bonferroni post hoc analysis).

Source data

Extended Data Fig. 3 Mutagenic analysis of the role of two mutations on AAVp2CV in generating mobile properties.

(a) Trajectory of three mutants: AAV1-647A, AAV1-647V, and AAV1-647Y was observed (PBS at pH 7.4). (b) The MSD of 647 site mutants was calculated and normalized to that of AAV1-647V. (c) Trajectory of three mutants: AAV1-430R, AAV1-430C, and AAV1-430E (PBS at pH 7.4). (d) MSD of 430 site mutants was measured and normalized to that of AAV1-430C. All data (n = 10) are presented as the mean ± STD.

Source data

Extended Data Fig. 4

Trajectories of AAVp2CV under different pH environments and comparison of MSD (n = 10).

Source data

Supplementary information

Supplementary Information

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Full-length unprocessed western blots.

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Kim, Y., Yeo, Y., Kim, M. et al. A highly mobile adeno-associated virus targeting vascular smooth muscle cells for the treatment of pulmonary arterial hypertension. Nat. Biomed. Eng 9, 1418–1436 (2025). https://doi.org/10.1038/s41551-025-01379-8

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