Novel PEI-aldehyde conjugates for gene delivery: Promoting chondrogenic differentiation in human mesenchymal stem cells.
| Title: | Novel PEI-aldehyde conjugates for gene delivery: Promoting chondrogenic differentiation in human mesenchymal stem cells. |
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| Authors: | Miranda-Balbuena D; Centro Interdisciplinar de Química e Bioloxía - CICA, Universidade da Coruña, 15071 A Coruña, Spain.; Ramil-Bouzas A; Centro Interdisciplinar de Química e Bioloxía - CICA, Universidade da Coruña, 15071 A Coruña, Spain.; Doldán-Mata N; Centro Interdisciplinar de Química e Bioloxía - CICA, Universidade da Coruña, 15071 A Coruña, Spain.; López-Seijas J; Centro Interdisciplinar de Química e Bioloxía - CICA, Universidade da Coruña, 15071 A Coruña, Spain.; Departamento de Biología, Facultade de Ciencias, Universidade da Coruña, 15071 A Coruña, Spain.; Fafián-Labora J; Centro Interdisciplinar de Química e Bioloxía - CICA, Universidade da Coruña, 15071 A Coruña, Spain.; Departamento de Fisioterapia, Medicina y Ciencias Biomédicas, Facultad de Ciencias de la Salud, Universidade da Coruña (UDC), Instituto de Investigación Biomédica de A Coruña (INIBIC), Complexo Hospitalario Universitario de A Coruña (CHUAC), Servizo Galego de Saúde (SERGAS), 15006 A Coruña, Spain.; Lamas-Criado I; Departamento de Biología, Facultade de Ciencias, Universidade da Coruña, 15071 A Coruña, Spain.; Caeiro-Rey JR; Departamento de Cirugía Ortopédica y Traumatología, Complexo Hospitalario Universitario de Santiago de Compostela (CHUS), Universidade de Santiago de Compostela (USC), 15706 Santiago de Compostela, Spain.; Fernández-Trillo P; Centro Interdisciplinar de Química e Bioloxía - CICA, Universidade da Coruña, 15071 A Coruña, Spain.; Departamento de Química, Facultade de Ciencias, Universidade da Coruña, 15071 A Coruña, Spain.; Rey-Rico A; Centro Interdisciplinar de Química e Bioloxía - CICA, Universidade da Coruña, 15071 A Coruña, Spain.; Departamento de Biología, Facultade de Ciencias, Universidade da Coruña, 15071 A Coruña, Spain. |
| Source: | Molecular therapy. Nucleic acids [Mol Ther Nucleic Acids] 2025 Apr 29; Vol. 36 (2), pp. 102551. Date of Electronic Publication: 2025 Apr 29 (Print Publication: 2025). |
| Publication Type: | Journal Article |
| Language: | English |
| Journal Info: | Publisher: Cell Press Country of Publication: United States NLM ID: 101581621 Publication Model: eCollection Cited Medium: Print ISSN: 2162-2531 (Print) Linking ISSN: 21622531 NLM ISO Abbreviation: Mol Ther Nucleic Acids Subsets: PubMed not MEDLINE |
| Imprint Name(s): | Publication: 2017- : Cambridge, MA : Cell Press; Original Publication: New York, NY : Nature Pub. Group |
| Abstract: | Mesenchymal stem cell (MSC) gene therapy holds significant potential for regenerative medicine, especially for treating conditions such as cartilage damage. Still, finding appropriate vectors to achieve a safe and efficient gene delivery remains a challenge. This study explores the development of novel polyethyleneimine (PEI)-based polymers functionalized with both cationic guanidinium and hydrophobic aldehyde groups for efficient transfection to human MSCs (hMSCs). PEI was chemically modified with guanidinium-(3-guanidin-N-(3-oxopropyl)propanamide [T1]) and 1-(4-formylphenyl)guanidine [T2]) and hydrophobic (octanal [T3A] and dodecanal [T3B]) aldehydes. Polyplexes were formed by the complexation of PEI-aldehyde conjugates with plasmids encoding for β-galactosidase (placZ), green fluorescent protein (pGFP), and the chondrogenic transcription factor SOX9 (psox9), and demonstrated efficient DNA complexation and protection. Among the formulations, PEI functionalized with the cationic (T2) and hydrophobic (T3A) aldehydes (PEIT2T3A) exhibited a superior transfection efficiency and biocompatibility, significantly enhancing the expression of target genes in hMSCs. Importantly, PEIT2T3A/psox9 polyplexes successfully promoted the chondrogenic differentiation of hMSCs, as evidenced by the increased expression of chondrogenic markers (SOX9, type-II collagen [COLII], and aggrecan [ACAN]) and proteoglycan deposition in aggregate cultures, while mitigating the low cell viability found with unmodified PEI. These findings suggest that PEIT2T3A is a promising non-viral vector for targeted gene delivery and hMSC-based regenerative medicine applications.; (© 2025 The Authors.) |
| Competing Interests: | The authors declare no competing interests. |
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| Contributed Indexing: | Keywords: Delivery Strategies; and chemical modification; biocompatibility; chondrogenic differentiation; gene therapy; human mesenchymal stem cells; plasmid DNA; polyethyleneimine; polyplexes; regenerative medicine |
| Entry Date(s): | Date Created: 20250609 Latest Revision: 20250611 |
| Update Code: | 20260130 |
| PubMed Central ID: | PMC12141052 |
| DOI: | 10.1016/j.omtn.2025.102551 |
| PMID: | 40487350 |
| Database: | MEDLINE |
Journal Article