{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,23]],"date-time":"2026-08-23T14:43:57Z","timestamp":1787496237925,"version":"build-2736575974"},"reference-count":44,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2022,11,4]],"date-time":"2022-11-04T00:00:00Z","timestamp":1667520000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81873844"],"award-info":[{"award-number":["81873844"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Bioengineering"],"abstract":"<jats:p>Placental angiogenesis disorder and placental dysplasia are important causes of many pregnancy complications. Due to safety and economic benefits, effective treatment strategies are currently limited. PFKFB3 is a key regulator of glycolysis that controls angiogenesis through a metabolic pathway independent of genetic signals. In this study, we constructed the nanodrug T-NPPFKFB3 and explored its feasibility to promote angiogenesis and enhance placental function. First, liposomes containing PFKFB3 overexpression plasmids modified by the placental homing peptide CGKRK were synthesized by the thin film method. In vivo experiments revealed that T-NPPFKFB3 injected intravenously specifically accumulated in the mouse placenta and therein upregulated the expression of PFKFB3 without affecting its expression in other important organs. In addition, T-NPPFKFB3 promoted placental angiogenesis and increased the fetal and placental weights of the mice. Finally, we evaluated the safety of T-NPPFKFB3. The expression levels of ALS\/AST\/BUN in the sera of pregnant mice were not significantly different from those in the sera of control group mice. However, T-NPPFKFB3 did not cause obvious fetal abnormalities or alter the average litter size. In conclusion, T-NPPFKFB3 can specifically target the placenta, promote angiogenesis, and enhance placental function without obvious side effects. Therefore, it has potential as a new strategy for the treatment of pregnancy complications.<\/jats:p>","DOI":"10.3390\/bioengineering9110652","type":"journal-article","created":{"date-parts":[[2022,11,7]],"date-time":"2022-11-07T02:43:51Z","timestamp":1667789031000},"page":"652","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Placenta-Targeted Nanoparticles Loaded with PFKFB3 Overexpression Plasmids Enhance Angiogenesis and Placental Function"],"prefix":"10.3390","volume":"9","author":[{"given":"Qi","family":"Li","sequence":"first","affiliation":[{"name":"Department of Reproductive Medicine, Xiangya Hospital, Central South University, Changsha 410008, China"},{"name":"Department of Obstetrics and Gynecology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoxia","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weifang","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wen","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Pain Treatment, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mengying","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhirui","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yin","family":"Zhao","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li","family":"Zou","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,11,4]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Zhang, B., Liang, R., Zheng, M., Cai, L., and Fan, X. (2019). Surface-functionalized nanoparticles as efficient tools in targeted therapy of pregnancy complications. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20153642"},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Stillbirth Collaborative Research Network Writing Group (2011). Causes of death among stillbirths. JAMA, 306, 2459\u20132468.","DOI":"10.1001\/jama.2011.1823"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"E24","DOI":"10.1152\/ajpendo.00379.2015","article-title":"The impact of a human IGF-II analog ([Leu27]IGF-II) on fetal growth in a mouse model of fetal growth restriction","volume":"310","author":"Charnock","year":"2016","journal-title":"Am. J. Physiol. Endocrinol. Metab."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1021","DOI":"10.1161\/HYPERTENSIONAHA.111.186270","article-title":"Sildenafil citrate rescues fetal growth in the catechol-O-methyl transferase knockout mouse model","volume":"59","author":"Stanley","year":"2012","journal-title":"Hypertension"},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Fisk, N.M., and Atun, R. (2008). Market failure and the poverty of new drugs in maternal health. PLoS Med., 5.","DOI":"10.1371\/journal.pmed.0050022"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"662","DOI":"10.1111\/j.1365-3156.2011.02778.x","article-title":"Relative and absolute addressability of global disease burden in maternal and perinatal health by investment in R&D","volume":"16","author":"Fisk","year":"2011","journal-title":"Trop. Med. Int. Health"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"671","DOI":"10.1161\/HYPERTENSIONAHA.117.10510","article-title":"TLR9 (Toll-Like Receptor 9) Agonist Suppresses Angiogenesis by Differentially Regulating VEGFA (Vascular Endothelial Growth Factor A) and sFLT1 (Soluble Vascular Endothelial Growth Factor Receptor 1) in Preeclampsia","volume":"71","author":"He","year":"2018","journal-title":"Hypertension"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1260","DOI":"10.1016\/j.placenta.2015.09.007","article-title":"Inhibition of human placental endothelial cell proliferation and angiogenesis by netrin-4","volume":"36","author":"Brouillet","year":"2015","journal-title":"Placenta"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1152\/physrev.00001.2017","article-title":"Endothelial cell metabolism","volume":"98","author":"Eelen","year":"2018","journal-title":"Physiol. Rev."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"651","DOI":"10.1016\/j.cell.2013.06.037","article-title":"Role of PFKFB3-driven glycolysis in vessel sprouting","volume":"154","author":"Georgiadou","year":"2013","journal-title":"Cell"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1016\/j.cmet.2013.11.008","article-title":"Partial and transient reduction of glycolysis by PFKFB3 blockade reduces pathological angiogenesis","volume":"19","author":"Schoors","year":"2014","journal-title":"Cell Metab."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1146\/annurev-physiol-021115-105134","article-title":"The link between angiogenesis and endothelial metabolism","volume":"79","author":"Potente","year":"2017","journal-title":"Annu. Rev. Physiol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1111\/j.1432-1033.1982.tb07039.x","article-title":"A kinetic study of pyrophosphate: Fructose-6-phosphate phosphotransferase from potato tubers. Application to a microassay of fructose 2,6-bisphosphate","volume":"129","author":"Lederer","year":"1982","journal-title":"Eur. J. Biochem."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"17044","DOI":"10.1038\/sigtrans.2017.44","article-title":"Roles of PFKFB3 in cancer","volume":"2","author":"Shi","year":"2017","journal-title":"Signal Transduct. Target Ther."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"897","DOI":"10.1016\/j.omtn.2021.01.005","article-title":"MALAT1 sponges miR-26a and miR-26b to regulate endothelial cell angiogenesis via PFKFB3-driven glycolysis in early-onset preeclampsia","volume":"23","author":"Li","year":"2021","journal-title":"Mol. Ther. Nucleic Acids"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"208","DOI":"10.1016\/j.canlet.2016.12.006","article-title":"Circular RNA profile identifies circPVT1 as a proliferative factor and prognostic marker in gastric cancer","volume":"388","author":"Chen","year":"2017","journal-title":"Cancer Lett."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1437","DOI":"10.2147\/IJN.S236927","article-title":"Nanocarrier-based therapeutics and theranostics drug delivery systems for next generation of liver cancer nanodrug modalities","volume":"15","author":"Ruman","year":"2020","journal-title":"Int. J. Nanomed."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"2434","DOI":"10.1056\/NEJMra0912273","article-title":"Nanomedicine","volume":"363","author":"Kim","year":"2010","journal-title":"N. Engl. J. Med."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"2235","DOI":"10.2217\/nnm-2016-0234","article-title":"Could peptide-decorated nanoparticles provide an improved approach for treating pregnancy complications?","volume":"11","author":"Harris","year":"2016","journal-title":"Nanomedicine"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"6548","DOI":"10.1039\/D0TB00612B","article-title":"Design of nanomaterials for applications in maternal\/fetal medicine","volume":"8","author":"Nelson","year":"2020","journal-title":"J. Mater. Chem. B"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"e1600349","DOI":"10.1126\/sciadv.1600349","article-title":"Tumor-homing peptides as tools for targeted delivery of payloads to the placenta","volume":"2","author":"King","year":"2016","journal-title":"Sci. Adv."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"2940","DOI":"10.7150\/thno.18845","article-title":"Placental Homing Peptide-microRNA Inhibitor Conjugates for Targeted Enhancement of Intrinsic Placental Growth Signaling","volume":"7","author":"Beards","year":"2017","journal-title":"Theranostics"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1231","DOI":"10.1161\/ATVBAHA.113.303041","article-title":"Endothelial PFKFB3 plays a critical role in angiogenesis","volume":"34","author":"Xu","year":"2014","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"628317","DOI":"10.3389\/fcell.2021.628317","article-title":"PFKFB3: A potential key to ocular angiogenesis","volume":"9","author":"Zhou","year":"2021","journal-title":"Front. Cell Dev. Biol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"3775","DOI":"10.3748\/wjg.v18.i29.3775","article-title":"Alanine and aspartate aminotransferase and glutamine-cycling pathway: Their roles in pathogenesis of metabolic syndrome","volume":"18","author":"Sookoian","year":"2012","journal-title":"World J. Gastroenterol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"85","DOI":"10.3389\/fphar.2016.00085","article-title":"Untargeted metabolomics reveals dose-response characteristics for effect of rhubarb in a rat model of cholestasis","volume":"7","author":"Zhang","year":"2016","journal-title":"Front. Pharmacol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"F939","DOI":"10.1152\/ajprenal.00025.2013","article-title":"Comparison of serum creatinine and serum cystatin C as biomarkers to detect sepsis-induced acute kidney injury and to predict mortality in CD-1 mice","volume":"307","author":"Leelahavanichkul","year":"2014","journal-title":"Am. J. Physiol. Renal. Physiol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1225","DOI":"10.3389\/fphys.2019.01225","article-title":"PINK1 deficiency ameliorates cisplatin-induced acute kidney injury in rats","volume":"10","author":"Zhou","year":"2019","journal-title":"Front. Physiol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1016\/j.ajog.2021.03.024","article-title":"Women and babies are dying from inertia: A collaborative framework for obstetrical drug development is urgently needed","volume":"225","author":"Out","year":"2021","journal-title":"Am. J. Obstet. Gynecol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"204","DOI":"10.1016\/j.ajog.2017.01.025","article-title":"Targeted nanoparticles in pregnancy: A new frontier in perinatal therapeutics","volume":"216","author":"Refuerzo","year":"2017","journal-title":"Am. J. Obstet. Gynecol."},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Ali, I., Alsehli, M., Scotti, L., Tullius Scotti, M., Tsai, S.T., Yu, R.S., Hsieh, M.F., and Chen, J.C. (2020). Progress in polymeric nano-medicines for theranostic cancer treatment. Polymers, 12.","DOI":"10.3390\/polym12030598"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"84","DOI":"10.1016\/j.jconrel.2015.05.005","article-title":"Development of a gene-activated scaffold platform for tissue engineering applications using chitosan-pDNA nanoparticles on collagen-based scaffolds","volume":"210","author":"Raftery","year":"2015","journal-title":"J. Control. Release"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"12320","DOI":"10.1002\/anie.201403036","article-title":"Engineered nanoparticles for drug delivery in cancer therapy","volume":"53","author":"Sun","year":"2014","journal-title":"Angew. Chem. Int. Ed. Engl."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1002\/wnan.167","article-title":"Regenerative nanomedicine and the treatment of degenerative retinal diseases","volume":"4","author":"Zarbin","year":"2012","journal-title":"Wiley Interdiscip. Rev. Nanomed. Nanobiotechnol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"687","DOI":"10.1080\/17435390.2017.1343875","article-title":"Silver nanoparticles inhaled during pregnancy reach and affect the placenta and the foetus","volume":"11","author":"Campagnolo","year":"2017","journal-title":"Nanotoxicology"},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Mottola, F., Iovine, C., Santonastaso, M., Romeo, M.L., Pacifico, S., Cobellis, L., and Rocco, L. (2019). NPs-TiO2 and lincomycin coexposure induces DNA damage in cultured human amniotic cells. Nanomaterials, 9.","DOI":"10.3390\/nano9111511"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"2229","DOI":"10.2217\/nnm.15.48","article-title":"Therapeutic and safety considerations of nanoparticle-mediated drug delivery in pregnancy","volume":"10","author":"Keelan","year":"2015","journal-title":"Nanomedicine"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1016\/j.placenta.2019.02.002","article-title":"The untapped potential of placenta-enriched molecules for diagnostic and therapeutic development","volume":"84","author":"Whigham","year":"2019","journal-title":"Placenta"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"6205","DOI":"10.1093\/nar\/19.22.6205","article-title":"The variability in activity of the universally expressed human cytomegalovirus immediate early gene 1 enhancer\/promoter in transgenic mice","volume":"19","author":"Furth","year":"1991","journal-title":"Nucleic Acids Res."},{"key":"ref_40","first-page":"4406","article-title":"The cytomegalovirus enhancer: A pan-active control element in transgenic mice","volume":"10","author":"Schmidt","year":"1990","journal-title":"Mol. Cell. Biol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.ejpb.2008.03.013","article-title":"Evaluation of promoter strength in mouse and rat primary hepatocytes using adenovirus vectors","volume":"70","author":"Arita","year":"2008","journal-title":"Eur. J. Pharm. Biopharm."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"280","DOI":"10.1093\/humupd\/dmaa049","article-title":"Nanoparticles in pregnancy: The next frontier in reproductive therapeutics","volume":"27","author":"Pritchard","year":"2021","journal-title":"Hum. Reprod. Update"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"S34","DOI":"10.1016\/j.placenta.2012.10.011","article-title":"Review: Transport across the placenta of mice and women","volume":"34","author":"Dilworth","year":"2013","journal-title":"Placenta"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"R81","DOI":"10.1530\/JOE-17-0185","article-title":"Treating the dysfunctional placenta","volume":"234","author":"Sibley","year":"2017","journal-title":"J. Endocrinol."}],"container-title":["Bioengineering"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2306-5354\/9\/11\/652\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T01:10:59Z","timestamp":1760145059000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2306-5354\/9\/11\/652"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,11,4]]},"references-count":44,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2022,11]]}},"alternative-id":["bioengineering9110652"],"URL":"https:\/\/doi.org\/10.3390\/bioengineering9110652","relation":{},"ISSN":["2306-5354"],"issn-type":[{"value":"2306-5354","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,11,4]]}}}