Gene Therapy for Inflammatory Cascade in Intrauterine Injury with Engineered Extracellular Vesicles Hybrid Snail Mucus‐enhanced Adhesive Hydrogels
Abstract Early hyper‐inflammation caused by intrauterine injury triggered subsequent intrauterine adhesion (IUA). STAT1‐mediated M1 macrophages are confirmed to secrete pro‐inflammatory cytokines to accelerate inflammatory cascade and IUA formation by multi‐omics analysis and experimental verificati...
Saved in:
| Main Authors: | , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Wiley
2025-01-01
|
| Series: | Advanced Science |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/advs.202410769 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1841553176299307008 |
|---|---|
| author | Xiaotong Peng Tao Wang Bo Dai Yiping Zhu Mei Ji Pusheng Yang Jiaxin Zhang Wenwen Liu Yaxin Miao Yonghang Liu Shuo Wang Jing Sun |
| author_facet | Xiaotong Peng Tao Wang Bo Dai Yiping Zhu Mei Ji Pusheng Yang Jiaxin Zhang Wenwen Liu Yaxin Miao Yonghang Liu Shuo Wang Jing Sun |
| author_sort | Xiaotong Peng |
| collection | DOAJ |
| description | Abstract Early hyper‐inflammation caused by intrauterine injury triggered subsequent intrauterine adhesion (IUA). STAT1‐mediated M1 macrophages are confirmed to secrete pro‐inflammatory cytokines to accelerate inflammatory cascade and IUA formation by multi‐omics analysis and experimental verification. However, clinically used hyaluronic acid (HA) hydrogels are prone to slip out of injury sites due to poor bio‐adhesion properties. Therefore, there are still challenges in applying hydrogels for M1 macrophage intervention in IUA treatment. Herein, an engineered extracellular vesicles (EVs) hybrid snail mucus (SM)‐enhanced adhesive hydrogels to improve bio‐adhesion property is fabricated and M1 macrophage intervention through targeting delivery and STAT1 silencing is achieved. First, inspired by the high bio‐adhesion capacity of SM, SM and gelatin methacrylate (GelMA) solution are mixed to construct GelMA/SM (GS) hydrogel. Then, folic acid‐modified extracellular vesicles (FA‐EVs) are synthesized for targeting the delivery of STAT1‐siRNA. Upon injection of FA‐EVs hybrid GS hydrogel into the uterine cavity, a protective hydrogel layer forms on the surface of injury sites and sustains the release of STAT1‐siRNA‐loaded FA‐EVs to curtail M1 macrophages generation through inhibiting STAT1 phosphorylation, resulting in reduction of myofibroblasts activation and collagen deposition. In addition, the pregnancy rate and the number of fetuses in rats treated with this hydrogel were much higher than those in other groups, suggesting that the hydrogel could promote functional endometrial regeneration and restore fertility. Overall, this study presents a promising strategy for employing FA‐EVs hybrid adhesive hydrogel with superior bio‐adhesion properties and M1 macrophage targeting delivery for IUA treatment and uterus recovery. |
| format | Article |
| id | doaj-art-b6fd8956e9e841cd8a609b2603fb5f7f |
| institution | Kabale University |
| issn | 2198-3844 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Wiley |
| record_format | Article |
| series | Advanced Science |
| spelling | doaj-art-b6fd8956e9e841cd8a609b2603fb5f7f2025-01-09T11:44:46ZengWileyAdvanced Science2198-38442025-01-01121n/an/a10.1002/advs.202410769Gene Therapy for Inflammatory Cascade in Intrauterine Injury with Engineered Extracellular Vesicles Hybrid Snail Mucus‐enhanced Adhesive HydrogelsXiaotong Peng0Tao Wang1Bo Dai2Yiping Zhu3Mei Ji4Pusheng Yang5Jiaxin Zhang6Wenwen Liu7Yaxin Miao8Yonghang Liu9Shuo Wang10Jing Sun11Department of Gynecology Shanghai Key Laboratory of Maternal Fetal Medicine Shanghai Institute of Maternal‐Fetal Medicine and Gynecologic Oncology Shanghai First Maternity and Infant Hospital School of Medicine Tongji University Shanghai 200092 ChinaDepartment of Gynecology Shanghai Key Laboratory of Maternal Fetal Medicine Shanghai Institute of Maternal‐Fetal Medicine and Gynecologic Oncology Shanghai First Maternity and Infant Hospital School of Medicine Tongji University Shanghai 200092 ChinaDepartment of Hematology Huashan Hospital Fudan University Shanghai 200040 ChinaDepartment of Gynecology Shanghai Key Laboratory of Maternal Fetal Medicine Shanghai Institute of Maternal‐Fetal Medicine and Gynecologic Oncology Shanghai First Maternity and Infant Hospital School of Medicine Tongji University Shanghai 200092 ChinaDepartment of Gynecology Shanghai Key Laboratory of Maternal Fetal Medicine Shanghai Institute of Maternal‐Fetal Medicine and Gynecologic Oncology Shanghai First Maternity and Infant Hospital School of Medicine Tongji University Shanghai 200092 ChinaDepartment of Gynecology Shanghai Key Laboratory of Maternal Fetal Medicine Shanghai Institute of Maternal‐Fetal Medicine and Gynecologic Oncology Shanghai First Maternity and Infant Hospital School of Medicine Tongji University Shanghai 200092 ChinaDepartment of Gynecology Shanghai Key Laboratory of Maternal Fetal Medicine Shanghai Institute of Maternal‐Fetal Medicine and Gynecologic Oncology Shanghai First Maternity and Infant Hospital School of Medicine Tongji University Shanghai 200092 ChinaDepartment of Gynecology Shanghai Key Laboratory of Maternal Fetal Medicine Shanghai Institute of Maternal‐Fetal Medicine and Gynecologic Oncology Shanghai First Maternity and Infant Hospital School of Medicine Tongji University Shanghai 200092 ChinaDepartment of Gynecology Shanghai Key Laboratory of Maternal Fetal Medicine Shanghai Institute of Maternal‐Fetal Medicine and Gynecologic Oncology Shanghai First Maternity and Infant Hospital School of Medicine Tongji University Shanghai 200092 ChinaSchool of Pharmacy and State Key Laboratory of Quality Research in Chinese Medicine Macau University of Science and Technology Macao 999078 ChinaDepartment of Orthopaedics Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine Shanghai 200233 ChinaDepartment of Gynecology Shanghai Key Laboratory of Maternal Fetal Medicine Shanghai Institute of Maternal‐Fetal Medicine and Gynecologic Oncology Shanghai First Maternity and Infant Hospital School of Medicine Tongji University Shanghai 200092 ChinaAbstract Early hyper‐inflammation caused by intrauterine injury triggered subsequent intrauterine adhesion (IUA). STAT1‐mediated M1 macrophages are confirmed to secrete pro‐inflammatory cytokines to accelerate inflammatory cascade and IUA formation by multi‐omics analysis and experimental verification. However, clinically used hyaluronic acid (HA) hydrogels are prone to slip out of injury sites due to poor bio‐adhesion properties. Therefore, there are still challenges in applying hydrogels for M1 macrophage intervention in IUA treatment. Herein, an engineered extracellular vesicles (EVs) hybrid snail mucus (SM)‐enhanced adhesive hydrogels to improve bio‐adhesion property is fabricated and M1 macrophage intervention through targeting delivery and STAT1 silencing is achieved. First, inspired by the high bio‐adhesion capacity of SM, SM and gelatin methacrylate (GelMA) solution are mixed to construct GelMA/SM (GS) hydrogel. Then, folic acid‐modified extracellular vesicles (FA‐EVs) are synthesized for targeting the delivery of STAT1‐siRNA. Upon injection of FA‐EVs hybrid GS hydrogel into the uterine cavity, a protective hydrogel layer forms on the surface of injury sites and sustains the release of STAT1‐siRNA‐loaded FA‐EVs to curtail M1 macrophages generation through inhibiting STAT1 phosphorylation, resulting in reduction of myofibroblasts activation and collagen deposition. In addition, the pregnancy rate and the number of fetuses in rats treated with this hydrogel were much higher than those in other groups, suggesting that the hydrogel could promote functional endometrial regeneration and restore fertility. Overall, this study presents a promising strategy for employing FA‐EVs hybrid adhesive hydrogel with superior bio‐adhesion properties and M1 macrophage targeting delivery for IUA treatment and uterus recovery.https://doi.org/10.1002/advs.202410769adhesive hydrogelsextracellular vesiclesgene therapyintrauterine adhesionsmacrophage polarization |
| spellingShingle | Xiaotong Peng Tao Wang Bo Dai Yiping Zhu Mei Ji Pusheng Yang Jiaxin Zhang Wenwen Liu Yaxin Miao Yonghang Liu Shuo Wang Jing Sun Gene Therapy for Inflammatory Cascade in Intrauterine Injury with Engineered Extracellular Vesicles Hybrid Snail Mucus‐enhanced Adhesive Hydrogels Advanced Science adhesive hydrogels extracellular vesicles gene therapy intrauterine adhesions macrophage polarization |
| title | Gene Therapy for Inflammatory Cascade in Intrauterine Injury with Engineered Extracellular Vesicles Hybrid Snail Mucus‐enhanced Adhesive Hydrogels |
| title_full | Gene Therapy for Inflammatory Cascade in Intrauterine Injury with Engineered Extracellular Vesicles Hybrid Snail Mucus‐enhanced Adhesive Hydrogels |
| title_fullStr | Gene Therapy for Inflammatory Cascade in Intrauterine Injury with Engineered Extracellular Vesicles Hybrid Snail Mucus‐enhanced Adhesive Hydrogels |
| title_full_unstemmed | Gene Therapy for Inflammatory Cascade in Intrauterine Injury with Engineered Extracellular Vesicles Hybrid Snail Mucus‐enhanced Adhesive Hydrogels |
| title_short | Gene Therapy for Inflammatory Cascade in Intrauterine Injury with Engineered Extracellular Vesicles Hybrid Snail Mucus‐enhanced Adhesive Hydrogels |
| title_sort | gene therapy for inflammatory cascade in intrauterine injury with engineered extracellular vesicles hybrid snail mucus enhanced adhesive hydrogels |
| topic | adhesive hydrogels extracellular vesicles gene therapy intrauterine adhesions macrophage polarization |
| url | https://doi.org/10.1002/advs.202410769 |
| work_keys_str_mv | AT xiaotongpeng genetherapyforinflammatorycascadeinintrauterineinjurywithengineeredextracellularvesicleshybridsnailmucusenhancedadhesivehydrogels AT taowang genetherapyforinflammatorycascadeinintrauterineinjurywithengineeredextracellularvesicleshybridsnailmucusenhancedadhesivehydrogels AT bodai genetherapyforinflammatorycascadeinintrauterineinjurywithengineeredextracellularvesicleshybridsnailmucusenhancedadhesivehydrogels AT yipingzhu genetherapyforinflammatorycascadeinintrauterineinjurywithengineeredextracellularvesicleshybridsnailmucusenhancedadhesivehydrogels AT meiji genetherapyforinflammatorycascadeinintrauterineinjurywithengineeredextracellularvesicleshybridsnailmucusenhancedadhesivehydrogels AT pushengyang genetherapyforinflammatorycascadeinintrauterineinjurywithengineeredextracellularvesicleshybridsnailmucusenhancedadhesivehydrogels AT jiaxinzhang genetherapyforinflammatorycascadeinintrauterineinjurywithengineeredextracellularvesicleshybridsnailmucusenhancedadhesivehydrogels AT wenwenliu genetherapyforinflammatorycascadeinintrauterineinjurywithengineeredextracellularvesicleshybridsnailmucusenhancedadhesivehydrogels AT yaxinmiao genetherapyforinflammatorycascadeinintrauterineinjurywithengineeredextracellularvesicleshybridsnailmucusenhancedadhesivehydrogels AT yonghangliu genetherapyforinflammatorycascadeinintrauterineinjurywithengineeredextracellularvesicleshybridsnailmucusenhancedadhesivehydrogels AT shuowang genetherapyforinflammatorycascadeinintrauterineinjurywithengineeredextracellularvesicleshybridsnailmucusenhancedadhesivehydrogels AT jingsun genetherapyforinflammatorycascadeinintrauterineinjurywithengineeredextracellularvesicleshybridsnailmucusenhancedadhesivehydrogels |