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

YZ Hu and SY Tzeng and L Cheng and JH Lin and A Villabona-Rueda and S Yu and SX Li and Z Schneiderman and YN Zhu and JY Ma and DR Wilson and SR Shannon and T Warren and Y Rui and CH Qiu and EW Kavanagh and KM Luly and YC Zhang and N Korinetz and FR D'Alessio and TH Wang and E Kokkoli and SK Reddy and E Luijten and JJ Green and HQ Mao, PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 121, e2400194121 (2024).

DOI: 10.1073/pnas.2400194121

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.

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