College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China.
Liangzhu Laboratory, Zhejiang University, Hangzhou, 311121, China.
Angew Chem Int Ed Engl. 2024 Jun 21;63(26):e202405444. doi: 10.1002/anie.202405444. Epub 2024 May 21.
Unlocking the full potential of mRNA immunotherapy necessitates targeted delivery to specific cell subsets in the spleen. Four-component lipid nanoparticles (LNPs) utilized in numerous clinical trials are primarily limited in hepatocyte and muscular targeting, highlighting the imperative demand for targeted and simplified non-liver mRNA delivery systems. Herein, we report the rational design of one-component ionizable cationic lipids to selectively deliver mRNA to the spleen and T cells with high efficacy. Unlike the tertiary amine-based ionizable lipids involved in LNPs, the proposed cationic lipids rich in secondary amines can efficiently deliver mRNA both in vitro and in vivo as the standalone carriers. Furthermore, these vectors facilitate efficacious mRNA delivery to the T cell subsets following intravenous administration, demonstrating substantial potential for advancing immunotherapy applications. This straightforward strategy extends the utility of lipid family for extrahepatic mRNA delivery, offering new insights into vector development beyond LNPs to further the field of precise mRNA therapy.
解锁 mRNA 免疫疗法的全部潜力需要将其靶向递送至脾脏中的特定细胞亚群。在许多临床试验中使用的四组分脂质纳米颗粒（LNPs）主要局限于肝细胞和肌肉靶向，这突出表明需要靶向和简化的非肝脏 mRNA 递送系统。在此，我们报告了一种单一组分可离子化阳离子脂质的合理设计，该脂质可选择性地将 mRNA 高效递送至脾脏和 T 细胞。与 LNPs 中涉及的基于叔胺的可离子化脂质不同，富含仲胺的所提出的阳离子脂质可作为独立载体在体外和体内有效地递送 mRNA。此外，这些载体在静脉内给药后可有效地将 mRNA 递送至 T 细胞亚群，为推进免疫疗法应用提供了巨大潜力。这种简单的策略扩展了脂质家族用于肝外 mRNA 递送的用途，为超越 LNPs 的向量开发提供了新的见解，以进一步推进精确 mRNA 疗法领域。
