Screening Libraries to Discover Molecular Design Principles for the Targeted Delivery of mRNA with One-Component Ionizable Amphiphilic Janus Dendrimers Derived from Plant Phenolic Acids

Abstract

Viral and synthetic vectors to deliver nucleic acids were key to the rapid development of extraordinarily efficient COVID-19 vaccines. The four-component lipid nanoparticles (LNPs), containing phospholipids, PEG-conjugated lipids, cholesterol, and ionizable lipids, co-assembled with mRNA via a microfluidic technology, are the leading nonviral delivery vector used by BioNTech/Pfizer and Moderna to access COVID-19 mRNA vaccines. LNPs exhibit a statistical distribution of their four components when delivering mRNA. Here, we report a methodology that involves screening libraries to discover the molecular design principles required to realize organ-targeted mRNA delivery and mediate activity with a one-component ionizable multifunctional amphiphilic Janus dendrimer (IAJD) derived from plant phenolic acids. IAJDs co-assemble with mRNA into monodisperse dendrimersome nanoparticles (DNPs) with predictable dimensions, via the simple injection of their ethanol solution in a buffer. The precise location of the functional groups in one-component IAJDs demonstrated that the targeted organs, including the liver, spleen, lymph nodes, and lung, are selected based on the hydrophilic region, while activity is associated with the hydrophobic domain of IAJDs. These principles, and a mechanistic hypothesis to explain activity, simplify the synthesis of IAJDs, the assembly of DNPs, handling, and storage of vaccines, and reduce price, despite employing renewable plant starting materials. Using simple molecular design principles will lead to increased accessibility to a large diversity of mRNA-based vaccines and nanotherapeutics.

From Frank–Kasper, Quasicrystals, and Biological Membrane Mimics to Reprogramming In Vivo the Living Factory to Target the Delivery of mRNA with One-Component Amphiphilic Janus Dendrimers

“…During the Covid-19 pandemic, our laboratory, together with the Weissman laboratory, developed and, starting in 2021, reported the first one-component IAJD systems that provided targeted delivery to spleen and lymph nodes, liver, and lung (Figures and ). − A diversity of primary structures of IAJDs were discovered, and methodologies to target different organs via their hydrophilic parts were elaborated. The overall activity and the distribution to different organs was designed via the structure of their hydrophobic parts .…”

“…The overall activity and the distribution to different organs was designed via the structure of their hydrophobic parts. 232 Although IAJDs are in the early stage of development, their less complex synthesis, lower price, simple assembly and coassembly with mRNA, and increased stability compared with the four-component counterparts bring them to the forefront of targeted delivery platform methods to address current and future vaccines and therapeutics for cancer and degenerative and infectious diseases.…”

“…During the Covid-19 pandemic, our laboratory, together with the Weissman laboratory, developed and, starting in 2021, reported the first one-component IAJD systems that provided targeted delivery to spleen and lymph nodes, liver, and lung (Figures and ). − A diversity of primary structures of IAJDs were discovered, and methodologies to target different organs via their hydrophilic parts were elaborated. The overall activity and the distribution to different organs was designed via the structure of their hydrophobic parts . Although IAJDs are in the early stage of development, their less complex synthesis, lower price, simple assembly and coassembly with mRNA, and increased stability compared with the four-component counterparts bring them to the forefront of targeted delivery platform methods to address current and future vaccines and therapeutics for cancer and degenerative and infectious diseases.…”

“…Ref is Copyright 2022 American Chemical Society. Ref is Copyright 2023 The Author(s). Licensee MDPI, Basel, Switzerland.…”

Dendrimersomes: Biomedical applications

“…A methodology utilizing screening libraries was employed to discover the essential molecular design principles required for targeted mRNA delivery to organs and the facilitation of activity using a single-component ionizable multifunctional IAJD derived from plant phenolic acids. 35 These IAJDs co-assembled with mRNA, forming monodisperse DNPs with predictable dimensions through the straightforward process of injecting their ethanol solution into a buffer. The strategic placement of functional groups in the 1-component IAJDs demonstrated that hydrophilic regions determined the targeted organs, such as the liver, spleen, lymph nodes, and lungs, while the hydrophobic domain governed their activity.…”