Supramolecular assembly of polycation/mRNA nanoparticles and in vivo monocyte programming

• 成果类型: Article
• 署名作者: Hu, Yizong; Tzeng, Stephany Y.; Cheng, Leonardo; Lin, Jinghan; Villabona-Rueda, Andres; Yu, Shuai; Li, Sixuan; Schneiderman, Zachary; Zhu, Yining; Ma, Jingyao; Wilson, David R.; Shannon, Sydney R.; Warren, Tiarra; Rui, Yuan; Qiu, Chenhu; Kavanagh, Erin W.; Luly, Kathryn M.; Zhang, Yicheng; Korinetz, Nicole; D'Alessio, Franco R.; Wang, Tza-Huei; Kokkoli, Efrosin; Reddy, Sashank K.; Luijten, Erik; Green, Jordan J.; Mao, Hai-Quan
• 署名单位: Johns Hopkins University; Johns Hopkins University; Johns Hopkins University; Johns Hopkins University; Johns Hopkins University; Northwestern University; Johns Hopkins University; Johns Hopkins University; Johns Hopkins University; Johns Hopkins University; Johns Hopkins University; Northwestern University; Northwestern University; Northwestern University; Massachusetts Institute of Technology (MIT)
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-15128
• DOI: 10.1073/pnas.2400194121
• 发表日期: 2024-08-27
• 关键词: dendritic cells; size; differentiation; infection; responses; delivery; immunity; potency; DEFENSE; antigen

摘要

Size- dependent phagocytosis is a well- characterized phenomenon in monocytes and macrophages. However, this size effect for preferential gene delivery to these important cell targets has not been fully exploited because commonly adopted stabilization methods for electrostatically complexed nucleic acid nanoparticles, such as PEGylation and charge repulsion, typically arrest the vehicle size below 200 nm. Here, we bridge the technical gap in scalable synthesis of larger submicron gene delivery vehicles by electrostatic self- assembly of charged nanoparticles, facilitated by a polymer structurally designed to modulate internanoparticle Coulombic and van der Waals forces. Specifically, our strategy permits controlled assembly of small poly(beta-amino ester)/messenger ribonucleic acid (mRNA) nanoparticles into particles with a size that is kinetically tunable between 200 and 1,000 nm with high colloidal stability in physiological media. We found that assembled particles with an average size of 400 nm safely and most efficiently transfect monocytes following intravenous administration and mediate their differentiation into macrophages in the periphery. When a CpG adjuvant is co- loaded into the particles with an antigen mRNA, the monocytes differentiate into inflammatory dendritic cells and prime adaptive anticancer immunity in the tumor- draining lymph node. This platform technology offers a unique ligand- independent, particle- size- mediated strategy for preferential mRNA delivery and enables therapeutic paradigms via monocyte programming.