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Ole A. W. Haabeth, Timothy R. Blake, Colin J. McKinlay, Robert M. Waymouth, Paul A. Wender, and Ronald Levy
Significance
The
RNA delivery field is mostly focused on lipid nanoparticles (LNPs).
Although promising, LNPs have several limitations with respect to
pharmacokinetics, biodistribution, and toxicity. The mechanism of RNA
charge-altering releasable transporters (CART) delivery and release is
unique. It proceeds dynamically with a controllable change in physical
properties. Differing from all mRNA delivery systems, a key attribute of
CARTs is a charge-altering degradation mechanism, which transforms the
initial polycationic CART into neutral byproducts, thereby enabling
endosomal escape, release, and subsequent translation of the polyanionic
mRNA cargo. With this study, we introduce a potentially general
approach to therapeutic vaccination enabled by a dynamic drug-delivery
system (mRNA-CART) and demonstrate its utility in suppressing tumor
formation and in eliminating established tumors.
Abstract
In
vivo delivery of antigen-encoding mRNA is a promising approach to
personalized cancer treatment. The therapeutic efficacy of mRNA vaccines
is contingent on safe and efficient gene delivery, biological stability
of the mRNA, and the immunological properties of the vaccine. Here we describe the development and evaluation of a versatile and
highly efficient mRNA vaccine-delivery system that employs
charge-altering releasable transporters (CARTs) to deliver
antigen-coding mRNA to antigen-presenting cells (APCs). We demonstrate
in human peripheral blood mononuclear cells that CART vaccines can
activate a robust antigen-specific immune response against mRNA-encoded
viral epitopes. In an established mouse model, we demonstrate that CARTs
preferentially target professional APCs in secondary lymphoid organs
upon i.v. injections and target local APCs upon s.c. injection.Finally, we show that CARTs coformulated with mRNA and a Toll-like
receptor ligand simultaneously transfect and activate target cells to
generate an immune response that can treat and cure mice with large,
established tumors.