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靶向CGKRK的脂质纳米颗粒增强罗格列酮向胎盘的递送，以改善小鼠先兆子痫。

CGKRK-targeted lipid nanoparticles enhance rosiglitazone delivery to the placenta to ameliorate murine preeclampsia.

作者信息

Li Ke, Jia Xiaoyan, Guo Dawei, Wang Haiming, Shui Haonan, Qi Hongbo, Zhang Hua

机构信息

Department of Obstetrics and Gynecology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China.

State Key Laboratory of Maternal and Fetal Medicine of Chongqing Municipality, Chongqing Medical University, Chongqing 400016, China.

出版信息

iScience. 2025 Jul 2;28(8):112744. doi: 10.1016/j.isci.2025.112744. eCollection 2025 Aug 15.

DOI:10.1016/j.isci.2025.112744
PMID:40703437
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC12283557/
Abstract

Placenta-targeting nano-drugs have emerged as a safe and effective treatment option for preeclampsia (PE). Downregulation of peroxisome proliferator-activated receptor γ (PPARγ) induces dysfunctional placental trophoblasts and facilitates placental reactive oxygen species, which weakens the PGC1α/UCP2 oxidative stress pathway, causing PE symptoms. Herein, rosiglitazone (RGZ), as an effective PPARγ agonist, exhibited great potential in PE treatment. However, low solubility and nonspecific effect limit the clinical application. Therefore, this study presents CGKRK-modified and RGZ-loaded lipid nanoparticles (CRNPs), based on the specific binding of CGKRK to calreticulin highly expressed in human and mouse trophoblasts. CRNP alleviates excessive oxidative stress and improves placental development and fetal growth in L-NAME-induced PE mice. However, it does not cause maternal side effects or fetal malformation in pregnant mice injected with a high dose of CRNP through the tail vein. Consequently, the safe and effective delivery of CRNP optimizes the placental-targeting therapeutic strategy.

摘要

靶向胎盘的纳米药物已成为治疗子痫前期（PE）的一种安全有效的选择。过氧化物酶体增殖物激活受体γ（PPARγ）的下调会导致胎盘滋养层细胞功能失调，并促进胎盘活性氧的产生，这会削弱PGC1α/UCP2氧化应激途径，从而引发PE症状。在此，罗格列酮（RGZ）作为一种有效的PPARγ激动剂，在PE治疗中显示出巨大潜力。然而，低溶解度和非特异性作用限制了其临床应用。因此，本研究基于CGKRK与人及小鼠滋养层细胞中高表达的钙网蛋白的特异性结合，提出了CGKRK修饰的载RGZ脂质纳米粒（CRNP）。CRNP可减轻L-NAME诱导的PE小鼠的过度氧化应激，改善胎盘发育和胎儿生长。然而，通过尾静脉注射高剂量CRNP的妊娠小鼠并未出现母体副作用或胎儿畸形。因此，CRNP的安全有效递送优化了胎盘靶向治疗策略。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/398b/12283557/e51ad39e6a40/gr8.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/398b/12283557/283f3dc6d163/fx1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/398b/12283557/ad638518bb41/gr1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/398b/12283557/8d41d541e6af/gr2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/398b/12283557/8d8a906f7c98/gr3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/398b/12283557/68ed2046c875/gr4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/398b/12283557/4419d712d716/gr5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/398b/12283557/a4ff31053fac/gr6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/398b/12283557/c146d653905b/gr7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/398b/12283557/e51ad39e6a40/gr8.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/398b/12283557/283f3dc6d163/fx1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/398b/12283557/ad638518bb41/gr1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/398b/12283557/8d41d541e6af/gr2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/398b/12283557/8d8a906f7c98/gr3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/398b/12283557/68ed2046c875/gr4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/398b/12283557/4419d712d716/gr5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/398b/12283557/a4ff31053fac/gr6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/398b/12283557/c146d653905b/gr7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/398b/12283557/e51ad39e6a40/gr8.jpg

相似文献

[1]
CGKRK-targeted lipid nanoparticles enhance rosiglitazone delivery to the placenta to ameliorate murine preeclampsia.

iScience. 2025-7-2

[2]
Rosiglitazone-Mediated Activation of PPARγ Induces PlGF Expression in Trophoblast Cells.

Reprod Sci. 2025-4-28

[3]
The Black Book of Psychotropic Dosing and Monitoring.

Psychopharmacol Bull. 2024-7-8

[4]
Accuracy of placental growth factor alone or in combination with soluble fms-like tyrosine kinase-1 or maternal factors in detecting preeclampsia in asymptomatic women in the second and third trimesters: a systematic review and meta-analysis.

Am J Obstet Gynecol. 2023-9

[5]
NETs exacerbate placental inflammation and injury through high mobility group protein B1 during preeclampsia.

Placenta. 2025-1

[6]
The 36-week preeclampsia risk by the Fetal Medicine Foundation algorithm is associated with fetal compromise following induction of labor.

Am J Obstet Gynecol. 2025-7

[7]

2022-1

[8]
Use of biochemical tests of placental function for improving pregnancy outcome.

Cochrane Database Syst Rev. 2015-11-25

[9]
Stem cell insights into human trophoblast lineage differentiation.

Hum Reprod Update. 2016-9-2

[10]
Interventions affecting the nitric oxide pathway versus placebo or no therapy for fetal growth restriction in pregnancy.

Cochrane Database Syst Rev. 2023-7-10

本文引用的文献

[1]
Reprogramming the immunosuppressive tumor microenvironment through nanomedicine: an immunometabolism perspective.

EBioMedicine. 2024-9

[2]
EGFR-targeted ionizable lipid nanoparticles enhance in vivo mRNA delivery to the placenta.

J Control Release. 2024-7

[3]
Systematic development of ionizable lipid nanoparticles for placental mRNA delivery using a design of experiments approach.

Bioact Mater. 2023-12-22

[4]
Reduced Brain Cortex Angiogenesis in the Offspring of the Preeclampsia-Like Syndrome.

Hypertension. 2023-12

[5]
Orthogonal Design of Experiments for Engineering of Lipid Nanoparticles for mRNA Delivery to the Placenta.

Small. 2024-10

[6]
The dilemma of sodium intake in preeclampsia: beneficial or detrimental?

Nutr Rev. 2024-2-12

[7]
The role of DNA hydroxymethylation and TET enzymes in placental development and pregnancy outcome.

Clin Epigenetics. 2023-4-25

[8]
AMPK regulates homeostasis of invasion and viability in trophoblasts by redirecting glucose metabolism: Implications for pre-eclampsia.

Cell Prolif. 2023-2

[9]
miR21 modulates the Hippo signaling pathway via interference with PP2A Bβ to inhibit trophoblast invasion and cause preeclampsia.

Mol Ther Nucleic Acids. 2022-9-20

[10]
Preeclampsia associated changes in volume density of fetoplacental vessels in Chinese women and mouse model of preeclampsia.

Placenta. 2022-4

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