Kim Hyung Shik, Simpson Grant Gerald, Fei Fan, Garris Christopher, Weissleder Ralph
Center for Systems Biology, Massachusetts General Hospital, 185 Cambridge Street, CPZN, 5206, Boston, Massachusetts 02114, United States.
Department of Pathology, Massachusetts General Hospital, 55 Fruit Street, Boston, Massachusetts 02114, United States.
J Am Chem Soc. 2025 Apr 9;147(14):11766-11776. doi: 10.1021/jacs.4c14474. Epub 2025 Mar 26.
Ribonucleic acids (RNA) are commonly formulated into lipid nanoparticles (LNP) for in vivo use, but challenges exist with systemic delivery and low in vivo expression efficiency. Inspired by ribonucleoprotein complexes in cells, we created synthetic ribonucleocarbohydrate (RNC) complexes based on cyclodextrin nanoparticles with ferrocenyl fluorocarbons capable of carrying mRNA and additional small-molecule drug payloads, facilitating lysosomal escape and immune stimulation all in the same nanoparticle. We show that this strategy results in highly efficient myeloid cell targeting (dendritic cells and MHC expressing macrophages) and protein expression following systemic administration. The RNC platform should have broad applications in vaccine development, immunosuppression, and immunostimulation for various diseases.
核糖核酸（RNA）通常被制备成脂质纳米颗粒（LNP）用于体内应用，但在全身递送和低体内表达效率方面存在挑战。受细胞中核糖核蛋白复合物的启发，我们基于环糊精纳米颗粒与二茂铁基碳氟化合物创建了合成核糖碳水化合物（RNC）复合物，该复合物能够携带mRNA和额外的小分子药物有效载荷，在同一纳米颗粒中促进溶酶体逃逸和免疫刺激。我们表明，该策略在全身给药后可实现高效的髓系细胞靶向（树突状细胞和表达MHC的巨噬细胞）和蛋白质表达。RNC平台在各种疾病的疫苗开发、免疫抑制和免疫刺激方面应具有广泛的应用。
