Rahhal Nowras, Rentzsch Mareike, Seiser Saskia, Freystätter Christian, Elbe-Bürger Adelheid, Rademacher Christoph
Department of Pharmaceutical Sciences, University of Vienna, Vienna, Austria.
Department of Microbiology, Immunology and Genetics, University of Vienna, Max F. Perutz Labs, Vienna, Austria.
Nanoscale. 2025 Feb 13;17(7):4038-4046. doi: 10.1039/d4nr03638g.
Targeted delivery has emerged as a critical strategy in the development of novel therapeutics. The advancement of nanomedicine hinges on the safe and precise cell-specific delivery of protein-based therapeutics to the immune system. However, major challenges remain, such as developing an efficient delivery system, ensuring specificity, minimizing off-target effects, and attaining effective intracellular localization. Our strategy utilizes lipid-based nanoparticles conjugated with a glycomimetic ligand. These nanoparticles selectively bind to langerin, a C-type lectin receptor expressed on Langerhans cells in the skin. We opted for cytotoxic proteins, namely cytochrome c and saporin, as model proteins to showcase the potential of delivering intact proteins to Langerhans cells. These proteins are recognized for their ability to induce apoptosis upon entry into the cytosol. We observed specific killing of cells expressing langerin , and in primary Langerhans cells isolated from mouse and human skin with minimal off target effects. By delivering functional proteins within lipid nanoparticles to Langerhans cells, our approach offers new potential to deliver effective therapeutics with minimal side effects.
靶向递送已成为新型治疗药物开发中的一项关键策略。纳米医学的发展取决于将基于蛋白质的治疗药物安全、精确地递送至免疫系统中的特定细胞。然而，仍然存在重大挑战，例如开发高效的递送系统、确保特异性、将脱靶效应降至最低以及实现有效的细胞内定位。我们的策略利用与糖模拟配体缀合的脂质纳米颗粒。这些纳米颗粒选择性地结合朗格汉斯蛋白，这是一种在皮肤中的朗格汉斯细胞上表达的C型凝集素受体。我们选择细胞毒性蛋白，即细胞色素c和皂草素，作为模型蛋白，以展示将完整蛋白递送至朗格汉斯细胞的潜力。这些蛋白因其进入细胞质后诱导细胞凋亡的能力而闻名。我们观察到表达朗格汉斯蛋白的细胞被特异性杀伤，并且在从小鼠和人类皮肤分离的原代朗格汉斯细胞中具有最小的脱靶效应。通过将脂质纳米颗粒内的功能性蛋白递送至朗格汉斯细胞，我们的方法为以最小的副作用递送有效的治疗药物提供了新的潜力。
