iPSC-derived exosomes as amphotericin B carriers: a promising approach to combat cryptococcal meningitis
BackgroundCryptococcal meningitis (CM) is a significant global health issue, particularly affecting individuals with HIV. Amphotericin B (AmB) serves as the cornerstone treatment for CM; however, its clinical application is restricted due to limited penetration of the blood–brain barrier and associa...
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| Format: | Article |
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Frontiers Media S.A.
2025-02-01
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| Series: | Frontiers in Microbiology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fmicb.2025.1531425/full |
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| author | Jingyu Zhao Jingyu Zhao Wei Fang Yangjie Gao Jiquan Chen Guizhen Wang Julin Gu |
| author_facet | Jingyu Zhao Jingyu Zhao Wei Fang Yangjie Gao Jiquan Chen Guizhen Wang Julin Gu |
| author_sort | Jingyu Zhao |
| collection | DOAJ |
| description | BackgroundCryptococcal meningitis (CM) is a significant global health issue, particularly affecting individuals with HIV. Amphotericin B (AmB) serves as the cornerstone treatment for CM; however, its clinical application is restricted due to limited penetration of the blood–brain barrier and associated nephrotoxicity.ObjectiveThis study investigates the use of exosomes derived from induced pluripotent stem cells (iPSC-Exos) as carriers for AmB in treating CM, aiming to enhance therapeutic efficacy and safety and reduce AmB toxicity.MethodsExosomes were extracted from iPSC culture supernatants using ultrafiltration and ultracentrifugation. Their morphology and size were analyzed using transmission electron microscopy (TEM) and nanoparticle flow cytometry (nFCM). Purity was confirmed by Western blotting for markers CD9, CD63, and TSG101. AmB was loaded into iPSC-Exos using a co-incubation method. The cytotoxicity of the iPSC-Exo/AmB complex was evaluated on HEK 293 T and RAW264.7 cells using the CCK-8 assay, while apoptosis was assessed using live/dead cell staining and flow cytometry. The hemolytic effects were tested using rabbit red blood cells. In a C57BL/6 J mouse model of cryptococcal infection, treatment groups (AmB, iPSC-Exo/AmB, and iPSC-Exo) were administered corresponding drugs, with blood and brain samples collected for analysis. The minimum inhibitory concentration (MIC) of iPSC-Exo/AmB and conventional AmB against Cryptococcus was determined.ResultsThe iPSC-Exo/AmB complex exhibited reduced cytotoxicity in vitro and decreased AmB-induced renal and hepatic toxicity in vivo. Its MIC against Cryptococcus was over eight times lower than conventional AmB, significantly reducing fungal burden in the mouse brain and lowering serum inflammatory factors.ConclusionThe iPSC-Exo/AmB complex is a promising therapeutic strategy that enhances AmB efficacy while reducing toxicity, offering new hope for treating CM and other refractory fungal infections of the central nervous system. |
| format | Article |
| id | doaj-art-330237e1c9c848309074d653370bb483 |
| institution | Kabale University |
| issn | 1664-302X |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Microbiology |
| spelling | doaj-art-330237e1c9c848309074d653370bb4832025-02-10T06:48:24ZengFrontiers Media S.A.Frontiers in Microbiology1664-302X2025-02-011610.3389/fmicb.2025.15314251531425iPSC-derived exosomes as amphotericin B carriers: a promising approach to combat cryptococcal meningitisJingyu Zhao0Jingyu Zhao1Wei Fang2Yangjie Gao3Jiquan Chen4Guizhen Wang5Julin Gu6Department of Dermatology, Third Affiliated Hospital of Naval Medical University, Shanghai, ChinaDepartment of Dermatology, The Third Affiliated Hospital of Soochow University, Changzhou, ChinaDepartment of Laser and Aesthetic Medicine, Shanghai Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, ChinaDepartment of Dermatology, Third Affiliated Hospital of Naval Medical University, Shanghai, ChinaDepartment of Pulmonary and Critical Care Medicine, Third Affiliated Hospital of Naval Medical University, Shanghai, ChinaDepartment of Emergency, Shanghai Tenth People’s Hospital, School of Medicine Tongji University, Shanghai, ChinaDepartment of Dermatology, Third Affiliated Hospital of Naval Medical University, Shanghai, ChinaBackgroundCryptococcal meningitis (CM) is a significant global health issue, particularly affecting individuals with HIV. Amphotericin B (AmB) serves as the cornerstone treatment for CM; however, its clinical application is restricted due to limited penetration of the blood–brain barrier and associated nephrotoxicity.ObjectiveThis study investigates the use of exosomes derived from induced pluripotent stem cells (iPSC-Exos) as carriers for AmB in treating CM, aiming to enhance therapeutic efficacy and safety and reduce AmB toxicity.MethodsExosomes were extracted from iPSC culture supernatants using ultrafiltration and ultracentrifugation. Their morphology and size were analyzed using transmission electron microscopy (TEM) and nanoparticle flow cytometry (nFCM). Purity was confirmed by Western blotting for markers CD9, CD63, and TSG101. AmB was loaded into iPSC-Exos using a co-incubation method. The cytotoxicity of the iPSC-Exo/AmB complex was evaluated on HEK 293 T and RAW264.7 cells using the CCK-8 assay, while apoptosis was assessed using live/dead cell staining and flow cytometry. The hemolytic effects were tested using rabbit red blood cells. In a C57BL/6 J mouse model of cryptococcal infection, treatment groups (AmB, iPSC-Exo/AmB, and iPSC-Exo) were administered corresponding drugs, with blood and brain samples collected for analysis. The minimum inhibitory concentration (MIC) of iPSC-Exo/AmB and conventional AmB against Cryptococcus was determined.ResultsThe iPSC-Exo/AmB complex exhibited reduced cytotoxicity in vitro and decreased AmB-induced renal and hepatic toxicity in vivo. Its MIC against Cryptococcus was over eight times lower than conventional AmB, significantly reducing fungal burden in the mouse brain and lowering serum inflammatory factors.ConclusionThe iPSC-Exo/AmB complex is a promising therapeutic strategy that enhances AmB efficacy while reducing toxicity, offering new hope for treating CM and other refractory fungal infections of the central nervous system.https://www.frontiersin.org/articles/10.3389/fmicb.2025.1531425/fullCryptococcus neoformanscryptococcal meningitisamphotericin Binduced pluripotent stem cellsdrug delivery systems |
| spellingShingle | Jingyu Zhao Jingyu Zhao Wei Fang Yangjie Gao Jiquan Chen Guizhen Wang Julin Gu iPSC-derived exosomes as amphotericin B carriers: a promising approach to combat cryptococcal meningitis Frontiers in Microbiology Cryptococcus neoformans cryptococcal meningitis amphotericin B induced pluripotent stem cells drug delivery systems |
| title | iPSC-derived exosomes as amphotericin B carriers: a promising approach to combat cryptococcal meningitis |
| title_full | iPSC-derived exosomes as amphotericin B carriers: a promising approach to combat cryptococcal meningitis |
| title_fullStr | iPSC-derived exosomes as amphotericin B carriers: a promising approach to combat cryptococcal meningitis |
| title_full_unstemmed | iPSC-derived exosomes as amphotericin B carriers: a promising approach to combat cryptococcal meningitis |
| title_short | iPSC-derived exosomes as amphotericin B carriers: a promising approach to combat cryptococcal meningitis |
| title_sort | ipsc derived exosomes as amphotericin b carriers a promising approach to combat cryptococcal meningitis |
| topic | Cryptococcus neoformans cryptococcal meningitis amphotericin B induced pluripotent stem cells drug delivery systems |
| url | https://www.frontiersin.org/articles/10.3389/fmicb.2025.1531425/full |
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