Li Ke, Jia Xiaoyan, Guo Dawei, Wang Haiming, Shui Haonan, Qi Hongbo, Zhang Hua
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.
iScience. 2025 Jul 2;28(8):112744. doi: 10.1016/j.isci.2025.112744. eCollection 2025 Aug 15.
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.
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。
