陆军军医大学张建祥等研究人员合作发现，新治疗靶点NCF1引导的多生物活性共轭疗法可预防早产和不良妊娠结局。2024年7月4日，《科学通报》杂志在线发表了这项成果。

研究人员对与早产（PTB）相关的人类和小鼠组织进行深入分析，结合细胞研究表明，异常高表达的中性粒细胞胞浆因子（NCF）1导致氧化胁迫、中性粒细胞和巨噬细胞的募集和促炎激活，而依次过表达的促炎介质会诱导子宫平滑肌细胞（USMC）的收缩以及USMC和羊膜上皮细胞的凋亡，从而导致PTB。根据这些新发现，研究人员合理设计了一种两亲性大分子共轭物LPA，通过共价结合低分子量肝素、反应性氧物质响应/清除成分和抗炎肽，制成了多活性纳米颗粒（LPA NP）。

在PTB的小鼠模型中，LPA NP通过调节NCF1介导的氧化-炎症级联反应有效延迟了PTB并抑制了不良妊娠结局，即减轻氧化应激，抑制炎性细胞激活，减少局部炎症，并减少子宫肌层细胞的收缩/凋亡。将LPA NP封装到温度响应、自愈和生物黏附的水凝胶中，在阴道给药后，通过延长滞留时间、持续释放纳米治疗和增加胎盘/子宫中的生物利用度，进一步增强了其体内功效。

重要的是，这种共轭物/纳米治疗和水凝胶制剂在妊娠小鼠中表现出极好的安全性，对母体和后代几乎没有副作用。

据介绍，PTB是全球新生儿发病率和死亡率的主要原因之一，但推动这种情况的细胞和分子机制仍未破解，从而限制了新疗法的发现。

附：英文原文

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

Author: Hongbo Qi a b, Jianxiang Zhang d f g

Issue&Volume: 2024/07/04

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 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 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 formulations exhibited excellent safety profiles in pregnant mice, with negligible side effects on the mother and offspring.

DOI: 10.1016/j.scib.2024.03.064

Source: https://www.sciencedirect.com/science/article/abs/pii/S209592732400478X