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
Juncheng Lu,
Elena N. Atochina-Vasserman,
Devendra S. Maurya,
Muhammad Irhash Shalihin,
Dapeng Zhang,
Srijay S. Chenna,
Jasper Adamson,
Matthew Liu,
Habib Ur Rehman Shah,
Honey Shah,
Qi Xiao,
Bryn Queeley,
Nathan A. Ona,
Erin K. Reagan,
Houping Ni,
Dipankar Sahoo,
Mihai Peterca,
Drew Weissman,
Virgil Percec
Affiliations
Juncheng Lu
Roy & Diana Vagelos Laboratories, Department of Chemistry, University of Pennsylvania, Philadelphia, PA 19104-6323, USA
Elena N. Atochina-Vasserman
Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104-6323, USA
Devendra S. Maurya
Roy & Diana Vagelos Laboratories, Department of Chemistry, University of Pennsylvania, Philadelphia, PA 19104-6323, USA
Muhammad Irhash Shalihin
Roy & Diana Vagelos Laboratories, Department of Chemistry, University of Pennsylvania, Philadelphia, PA 19104-6323, USA
Dapeng Zhang
Roy & Diana Vagelos Laboratories, Department of Chemistry, University of Pennsylvania, Philadelphia, PA 19104-6323, USA
Srijay S. Chenna
Roy & Diana Vagelos Laboratories, Department of Chemistry, University of Pennsylvania, Philadelphia, PA 19104-6323, USA
Jasper Adamson
Roy & Diana Vagelos Laboratories, Department of Chemistry, University of Pennsylvania, Philadelphia, PA 19104-6323, USA
Matthew Liu
Roy & Diana Vagelos Laboratories, Department of Chemistry, University of Pennsylvania, Philadelphia, PA 19104-6323, USA
Habib Ur Rehman Shah
Roy & Diana Vagelos Laboratories, Department of Chemistry, University of Pennsylvania, Philadelphia, PA 19104-6323, USA
Honey Shah
Roy & Diana Vagelos Laboratories, Department of Chemistry, University of Pennsylvania, Philadelphia, PA 19104-6323, USA
Qi Xiao
Roy & Diana Vagelos Laboratories, Department of Chemistry, University of Pennsylvania, Philadelphia, PA 19104-6323, USA
Bryn Queeley
Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104-6323, USA
Nathan A. Ona
Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104-6323, USA
Erin K. Reagan
Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104-6323, USA
Houping Ni
Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104-6323, USA
Dipankar Sahoo
Roy & Diana Vagelos Laboratories, Department of Chemistry, University of Pennsylvania, Philadelphia, PA 19104-6323, USA
Mihai Peterca
Roy & Diana Vagelos Laboratories, Department of Chemistry, University of Pennsylvania, Philadelphia, PA 19104-6323, USA
Drew Weissman
Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104-6323, USA
Virgil Percec
Roy & Diana Vagelos Laboratories, Department of Chemistry, University of Pennsylvania, Philadelphia, PA 19104-6323, USA
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.
