Safford Hannah C, Shuler Cecilia F, Geisler Hannah C, Thatte Ajay S, Swingle Kelsey L, Han Emily L, Murray Amanda M, Hamilton Alex G, Yamagata Hannah M, Mitchell Michael J
Department of Bioengineering, University of Pennsylvania, Philadelphia, Pennsylvania 19104, United States.
Department of Biophysics, University of Pennsylvania, Philadelphia, Pennsylvania 19104, United States.
Nano Lett. 2025 Mar 26;25(12):4800-4808. doi: 10.1021/acs.nanolett.4c06241. Epub 2025 Mar 14.
It is well established that the physicochemical properties of lipid nanoparticles (LNPs) can govern their interactions with various biological barriers. One property hypothesized to influence nanoparticle-cell interactions is elasticity. Here, we formulate LNPs with naturally occurring cholesterol analogs to tune LNP elasticity and study its role on mRNA delivery to the placenta. LNP elasticity was measured via atomic force microscopy where these LNPs exhibited Young's moduli ranging from 71.0 ± 26.2 to 411.4 ± 145.7 kPa. In vitro screening of these LNPs in placental trophoblasts showed that stiffer LNPs improved LNP uptake and mRNA delivery compared with softer LNPs. Following intravenous administration to pregnant mice, the stiffer LNPs incorporating β-sitosterol enhanced placental and reduced liver mRNA delivery compared with softer LNPs containing only cholesterol. These results demonstrate the ability of stiffer LNPs to promote placental mRNA delivery and highlight the potential of tuning LNP elasticity to improve LNP-mediated mRNA delivery to organs of interest.
脂质纳米颗粒（LNPs）的物理化学性质能够决定它们与各种生物屏障的相互作用，这一点已经得到了充分证实。一种被认为会影响纳米颗粒与细胞相互作用的性质是弹性。在这里，我们用天然存在的胆固醇类似物配制LNPs，以调节LNP的弹性，并研究其在mRNA传递至胎盘过程中的作用。通过原子力显微镜测量LNP的弹性，这些LNPs的杨氏模量范围为71.0±26.2至411.4±145.7 kPa。在胎盘滋养层细胞中对这些LNPs进行体外筛选表明，与较软的LNPs相比，较硬的LNPs能改善LNP摄取和mRNA传递。给怀孕小鼠静脉注射后，与仅含胆固醇的较软LNPs相比，掺入β-谷甾醇的较硬LNPs增强了胎盘的mRNA传递并减少了肝脏的mRNA传递。这些结果证明了较硬的LNPs促进胎盘mRNA传递的能力，并突出了调节LNP弹性以改善LNP介导的mRNA向感兴趣器官传递的潜力。
