Chen Moore Z, Yuen Daniel, McLeod Victoria M, Yong Ken W, Smyth Cameron H, Herling Bruna Rossi, Payne Thomas J, Fabb Stewart A, Belousoff Matthew J, Algarni Azizah, Sexton Patrick M, Porter Christopher J H, Pouton Colin W, Johnston Angus P R
Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia.
Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia.
Nat Nanotechnol. 2025 Sep;20(9):1273-1284. doi: 10.1038/s41565-025-01954-9. Epub 2025 Aug 4.
Efficient and precise delivery of mRNA is critical to advance mRNA therapies beyond their current use as vaccines. Lipid nanoparticles (LNPs) efficiently encapsulate and protect mRNA, but non-specific cellular uptake may lead to off-target delivery and minimal delivery to target cells. Functionalizing LNPs with antibodies enables targeted mRNA delivery, but traditional modification techniques require complex conjugation and purification, which often reduces antibody affinity. Here we present a simple method for capturing antibodies in their optimal orientation on LNPs, without antibody modification or complex purification. This strategy uses an optimally oriented anti-Fc nanobody on the LNP surface to capture antibodies, resulting in protein expression levels more than 1,000 times higher than non-targeted LNPs and more than 8 times higher than conventional antibody functionalization techniques. These precisely targeted LNPs showed highly efficient in vivo targeting to T cells, with minimal delivery to other immune cells. This approach enables the rapid development of targeted LNPs and has the potential to broaden the use of mRNA therapies.
将信使核糖核酸（mRNA）高效且精确地递送出去对于推动mRNA疗法超越目前作为疫苗的应用至关重要。脂质纳米颗粒（LNP）能够有效地包裹并保护mRNA，但非特异性的细胞摄取可能会导致脱靶递送，且向靶细胞的递送量极少。用抗体对LNP进行功能化可实现靶向mRNA递送，但传统的修饰技术需要复杂的偶联和纯化过程，这往往会降低抗体亲和力。在此，我们展示了一种简单的方法，可使抗体以最佳方向捕获在LNP上，无需对抗体进行修饰或进行复杂的纯化。该策略利用LNP表面以最佳方向排列的抗Fc纳米抗体来捕获抗体，从而使蛋白质表达水平比非靶向LNP高出1000多倍，比传统抗体功能化技术高出8倍以上。这些精确靶向的LNP在体内对T细胞具有高效靶向性，向其他免疫细胞的递送量极少。这种方法能够快速开发靶向LNP，并有可能扩大mRNA疗法的应用范围。
