Biodegradable lipophilic polymeric mRNA nanoparticles for ligand-free targeting of splenic dendritic cells for cancer vaccination

Nanoparticle (NP)-based mRNA cancer vaccines hold great promise to realize personalized cancer treatments. To advance this technology requires delivery formulations for efficient intracellular delivery to antigen-presenting cells. We developed a class of bioreducible lipophilic poly(beta-amino ester...

Full description

Saved in:
Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2023-06, Vol.120 (26), p.e2301606120
Main Authors: Ben-Akiva, Elana, Karlsson, Johan, Hemmati, Shayan, Yu, Hongzhe, Tzeng, Stephany Y, Pardoll, Drew M, Green, Jordan J
Format: Article
Language:English
Subjects:
Adenocarcinoma
Adenocarcinoma - pathology
Adjuvants
Adjuvants, Immunologic
Animal models
Animals
Antigen-presenting cells
Antigens
Biodegradation
Biological Sciences
Cancer
Cancer therapies
Cancer Vaccines
CD8 antigen
Colonic Neoplasms - pathology
Colonic Neoplasms - therapy
delivery
Dendritic Cells
Humans
Intravenous administration
Ligands
Lipids
Lipophilic
Lipophilicity
Lymphocytes
Lymphocytes T
Melanoma
Mice
mRNA
nanoparticle
Nanoparticles
Nanoparticles - chemistry
Nucleic acids
Physical Sciences
Polymers
Polymers - chemistry
RNA, Messenger - genetics
Self-assembly
Spleen
Structure-function relationships
Toll-like receptors
Transfection
Vaccination
vaccine
Vaccines
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Nanoparticle (NP)-based mRNA cancer vaccines hold great promise to realize personalized cancer treatments. To advance this technology requires delivery formulations for efficient intracellular delivery to antigen-presenting cells. We developed a class of bioreducible lipophilic poly(beta-amino ester) nanocarriers with quadpolymer architecture. The platform is agnostic to the mRNA sequence, with one-step self-assembly allowing for delivery of multiple antigen-encoding mRNAs as well as codelivery of nucleic acid-based adjuvants. We examined structure-function relationships for NP-mediated mRNA delivery to dendritic cells (DCs) and identified that a lipid subunit of the polymer structure was critical. Following intravenous administration, the engineered NP design facilitated targeted delivery to the spleen and preferential transfection of DCs without the need for surface functionalization with targeting ligands. Treatment with engineered NPs codelivering antigen-encoding mRNA and toll-like receptor agonist adjuvants led to robust antigen-specific CD8+ T cell responses, resulting in efficient antitumor therapy in in vivo models of murine melanoma and colon adenocarcinoma.
ISSN:0027-8424
1091-6490
1091-6490
DOI:10.1073/pnas.2301606120