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

Juan Cheng ¹Xiaoyan Jia ²Limei Yang ³Siqi Zhang ²Zhiyu Chen ⁴Qian Gui ³Ting Li ³Zedan Pu ³Hongbo Qi ⁵Jianxiang Zhang⁶

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作者信息

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

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 ther-apies.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 sequen-tially 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 cova-lently integrating low-molecular-weight heparin,a reactive oxygen species-responsive/scavenging com-ponent,and an anti-inflammatory peptide.This bioengineered macromolecular conjugate can self-assemble 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 oxidative-inflammatory 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 formu-lations exhibited excellent safety profiles in pregnant mice,with negligible side effects on the mother and offspring.

Key words

Preterm birth/Neutrophil cytoplasmic factor/Bioactive conjugate/Nanotherapy/Hydrogel therapy

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基金项目

National Natural Science Foundation of China(82301918)

Joint Funds of the National Natural Science Foundation of China(U21A20346)

Natural Science Foundation of Chongqing(CSTB2022NSCQ-MSX0856)

Key Program for Technological Innovation & Application Development of Chongqing(CSTB2022TIAD-KPX0156)

Key Medical Program Integrated by Chongqing Science and Technology Bureau and Chongqing Health Commission(2023GGXM005)

Program for Scientific and Technological Innovation Leader of Chongqing(CQYC20210302362)

出版年

2024

科学通报(英文版)

中国科学院

科学通报(英文版)

CSTPCD

ISSN：1001-6538

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