Functionally integrating nanoparticles alleviate deep vein thrombosis in pregnancy and rescue intrauterine growth restriction

• Published in: Nature communications Vol. 13; no. 1; pp. 7166 - 21
• Main Authors: Cheng, Juan, Zhang, Siqi, Li, Chenwen, Li, Ke, Jia, Xiaoyan, Wei, Quanfang, Qi, Hongbo, Zhang, Jianxiang
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 22.11.2022; Nature Publishing Group; Nature Portfolio
• Subjects: 13/31; 13/51; 14/19; 631/154/152; 631/61/350/354; 631/61/54/990; 64/86; 692/699/75/593/567; Animals; Bioavailability; Female; Fetal Growth Retardation - drug therapy; Fetuses; Fibrin; Heparin; Heparin, Low-Molecular-Weight - therapeutic use; Humanities and Social Sciences; Humans; Linoleic acid; Low molecular weights; Molecular weight; multidisciplinary; Nanoparticles; Occlusion; Oxidative stress; Platelet aggregation; Pregnancy; Rats; Science; Science (multidisciplinary); Tempol; Thromboembolism; Thrombolysis; Thrombolytic drugs; Thrombosis; Thrombosis - drug therapy; Veins; Veins & arteries; Venous Thrombosis - drug therapy
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-022-34878-2

There is still unmet demand for effective, safe, and patient-friendly anti-thrombotics to treat deep vein thrombosis (DVT) during pregnancy. Here we first engineer a bioactive amphiphile (TLH) by simultaneously conjugating Tempol and linoleic acid onto low molecular weight heparin (LMWH), which can assemble into multifunctional nanoparticles (TLH NP). In pregnant rats with DVT, TLH NP can target and dissolve thrombi, recanalize vessel occlusion, and eradicate the recurrence of thromboembolism, thereby reversing DVT-mediated intrauterine growth restriction and delayed development of fetuses. Mechanistically, therapeutic effects of TLH NP are realized by inhibiting platelet aggregation, facilitating thrombolysis, reducing local inflammation, attenuating oxidative stress, promoting endothelial repair, and increasing bioavailability. By decorating with a fibrin-binding peptide, targeting efficiency and therapeutic benefits of TLH NP are considerably improved. Importantly, LMWH nanotherapies show no toxicities to the mother and fetus at the dose 10-time higher than the examined therapeutic dosage. There is still an unmet need for effective and safe drugs to treat deep vein thrombosis during pregnancy, a life-threatening condition for the mother and fetus. Here, the authors show that engineered multifunctional nanoparticles can site-specifically dissolve thrombi and reverse deep vein thrombosis-mediated intrauterine growth restriction and delayed development of fetuses in pregnant rats.