New therapeutic target NCF1-directed multi-bioactive conjugate therapies prevent preterm birth and adverse pregnancy outcomes  

基于NCF1新靶点的多重生物活性偶联物疗法防治早产及不良妊娠结局

作　　者：Juan Cheng Xiaoyan Jia Limei Yang Siqi Zhang Zhiyu Chen Qian Gui Ting Li Zedan Pu Hongbo Qi Jianxiang Zhang 成娟;贾小燕;杨莉梅;张思祺;陈治宇;归倩;李婷;蒲泽丹;漆洪波;张建祥

机构地区：[1]Chongqing Key Laboratory of Maternal and Fetal Medicine,The First Affiliated Hospital of Chongqing Medical University,Chongqing 400016,China [2]Women and Children’s Hospital of Chongqing Medical University,Chongqing 401147,China [3]Department of Obstetrics,The First Affiliated Hospital of Chongqing Medical University,Chongqing 400016,China [4]Department of Pharmaceutics,College of Pharmacy,Third Military Medical University(Army Medical University),Chongqing 400038,China [5]Department of Orthopedics,The First Affiliated Hospital of Chongqing Medical University,Chongqing 400016,China [6]Yu-Yue Pathology Scientific Research Center,Chongqing 400039,China [7]State Key Laboratory of Trauma and Chemical Poisoning,Third Military Medical University(Army Medical University),Chongqing 400038,China

出　　处：《Science Bulletin》2024年第16期2604-2621,共18页科学通报（英文版）

基　　金：supported by the National Natural Science Foundation of China(82301918);Joint Funds of the National Natural Science Foundation of China(U21A20346);the Natural Science Foundation of Chongqing(CSTB2022NSCQ-MSX0856);the Key Program for Technological Innovation&Application Development of Chongqing(CSTB2022TIAD-KPX0156);the Key Medical Program Integrated by Chongqing Science and Technology Bureau and Chongqing Health Commission(2023GGXM005);the Program for Scientific and Technological Innovation Leader of Chongqing(CQYC20210302362).

摘　　要：Preterm birth(PTB)is a leading cause of neonatal morbidity and mortality worldwide,yet the cellular and molecular mechanisms driving this condition remain undeciphered,thus limiting discovery of new therapies.In-depth analyses of human and mouse tissues associated with PTB,in combination with cellular studies,indicated that aberrantly high-expressed neutrophil cytoplasmic factor(NCF)1 leads to oxidative distress,recruitment,and pro-inflammatory activation of neutrophils and macrophages,while sequentially overexpressed pro-inflammatory mediators induce contractions of uterine smooth muscle cells(USMCs)as well as apoptosis of USMCs and amniotic epithelial cells,thereby causing PTB.According to these new findings,we rationally engineered an amphiphilic macromolecular conjugate LPA by covalently integrating low-molecular-weight heparin,a reactive oxygen species-responsive/scavenging component,and an anti-inflammatory peptide.This bioengineered macromolecular conjugate can selfassemble into multi-bioactive nanoparticles(LPA NP).In a mouse model of PTB,LPA NP effectively delayed PTB and inhibited adverse pregnancy outcomes,by regulating NCF1-mediated oxidativeinflammatory cascades,i.e.,attenuating oxidative stress,inhibiting inflammatory cell activation,reducing local inflammation,and decreasing contraction/apoptosis of myometrial cells.Packaging LPA NP into temperature-responsive,self-healing,and bioadhesive hydrogel further potentiated its in vivo efficacies after intravaginal delivery,by prolonging retention time,sustaining nanotherapy release,and increasing bioavailability in the placenta/uterus.Importantly,both the conjugate/nanotherapy and hydrogel formulations exhibited excellent safety profiles in pregnant mice,with negligible side effects on the mother and offspring.

关 键 词：Preterm birth Neutrophil cytoplasmic factor Bioactive conjugate Nanotherapy Hydrogel therapy 

分 类 号：R714.2[医药卫生—妇产科学]