Han, Zhou, and Dwivedy et al. developed cationic α-helical polypeptides that can condense and stabilize encoding mRNA in nanosized polyplexes. Upon s.c. administration, these polyplexes are taken up by DCs in lymph nodes, induce activation by NF-κB, IRF, p-STING, and cGAS, and improve the processing and presentation of mRNA-encoded antigens compared to mRNA-LNP, lipoplexes, or free mRNA. In E.G7-OVA lymphoma and 4T1 TNBC models, polyplexes elicited potent neoantigen-specific CD8+ T cells, reprogrammed the TIME (enriching DCs, CD86+ macrophages, and CD8+ T cells), enhanced therapeutic efficacy, and synergized with anti-PD-1.
Contributed by Ute Burkhardt
ABSTRACT: mRNA-based vaccines have demonstrated tremendous success during the era of COVID-19, but its therapeutic potential for treating cancer, especially poorly immunogenic solid tumors, remains largely underachieved. Herein, we report a class of self-adjuvanting α-helical polypeptides that can dramatically improve the antitumor efficacy of tumor neoantigen-encoding mRNAs. The α-helical polypeptides can facilitate the intracellular delivery of mRNAs into dendritic cells (DCs), simultaneously activate DCs by regulating NF-κB and IRF pathways, and improve the ability of dendritic cells to process and present mRNA-encoded neoantigens. Molecular docking and simulation results also confirm the stable complexation between mRNA and α-helical polypeptides. The conceived polyplex, upon subcutaneous administration, can migrate to the draining lymph nodes and transfect and activate DCs in the lymph nodes, resulting in superior neoantigen-specific cytotoxic T lymphocyte response in vivo. Compared to conventional lipoplexes or SM102 lipid nanoparticle-based mRNA vaccines that yield 0% tumor-free survival, the polyplex yields 83.3% and 33.3% tumor-free survival against E.G7-OVA lymphoma and 4T1 triple negative breast cancer, respectively, among the best antitumor efficacy reported to date for mRNA cancer vaccines. The polyplex also reprograms the immunosuppressive tumor microenvironment, by stimulating and enriching DCs, M1-phenotype CD86+ macrophages, and CD8+ T cells in the tumors. We also observed the upregulated expression of Programmed Death-1 (PD-1) by intratumoral CD8+ T cells and PD-L1 by 4T1 tumor cells after polyplex treatment and further demonstrated the synergistic effect between polyplex vaccine and anti-PD-1 therapy. Our polyplex system provides a facile and generalizable approach to developing robust mRNA-based cancer vaccines.
Author Info: (1) Department of Materials Science and Engineering, University of Illinois at Urbana-Champaign, Urbana, IL 61801. (2) Department of Materials Science and Engineering, University o
Author Info: (1) Department of Materials Science and Engineering, University of Illinois at Urbana-Champaign, Urbana, IL 61801. (2) Department of Materials Science and Engineering, University of Illinois at Urbana-Champaign, Urbana, IL 61801. (3) Department of Bioengineering, University of Illinois at Urbana-Champaign, Urbana, IL 61801. (4) Department of Materials Science and Engineering, University of Illinois at Urbana-Champaign, Urbana, IL 61801. (5) Department of Materials Science and Engineering, University of Illinois at Urbana-Champaign, Urbana, IL 61801. (6) Department of Materials Science and Engineering, University of Illinois at Urbana-Champaign, Urbana, IL 61801. (7) Department of Bioengineering, University of Illinois at Urbana-Champaign, Urbana, IL 61801. (8) Department of Materials Science and Engineering, University of Illinois at Urbana-Champaign, Urbana, IL 61801. (9) Department of Materials Science and Engineering, University of Illinois at Urbana-Champaign, Urbana, IL 61801. (10) Department of Bioengineering, University of Illinois at Urbana-Champaign, Urbana, IL 61801. (11) Department of Materials Science and Engineering, University of Illinois at Urbana-Champaign, Urbana, IL 61801. (12) Department of Veterinary Clinical Medicine, University of Illinois at Urbana-Champaign, Urbana, IL 61801. (13) Alnylam Pharmaceuticals, Inc., Cambridge, MA 02142. (14) Department of Materials Science and Engineering, University of Illinois at Urbana-Champaign, Urbana, IL 61801. Department of Bioengineering, University of Illinois at Urbana-Champaign, Urbana, IL 61801. Cancer Center at Illinois, Urbana, IL 61801. Carle College of Medicine, University of Illinois at Urbana-Champaign, Urbana, IL (15) Zhejiang University-University of Edinburgh Institute, Zhejiang University School of Medicine, International Campus, Zhejiang University, Haining 314400, China. (16) Department of Materials Science and Engineering, University of Illinois at Urbana-Champaign, Urbana, IL 61801. Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, IL Beckman Institute for Advanced Science and Technology, University of Illinois at Urbana-Champaign, Urbana, IL 61801. Materials Research Laboratory, University of Illinois at Urbana-Champaign, Urbana, IL 61801. (17) Department of Materials Science and Engineering, University of Illinois at Urbana-Champaign, Urbana, IL 61801. Department of Bioengineering, University of Illinois at Urbana-Champaign, Urbana, IL 61801. Department of Electrical and Computer Engineering, University of Illinois at Urbana-Champaign, Urbana, IL 61801. (18) Department of Bioengineering, University of Illinois at Urbana-Champaign, Urbana, IL 61801. Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, IL Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, IL 61801. (19) Department of Materials Science and Engineering, University of Illinois at Urbana-Champaign, Urbana, IL 61801. Department of Bioengineering, University of Illinois at Urbana-Champaign, Urbana, IL 61801. Cancer Center at Illinois, Urbana, IL 61801. Carle College of Medicine, University of Illinois at Urbana-Champaign, Urbana, IL Beckman Institute for Advanced Science and Technology, University of Illinois at Urbana-Champaign, Urbana, IL 61801. Materials Research Laboratory, University of Illinois at Urbana-Champaign, Urbana, IL 61801. Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, IL 61801.
