Advances in Nonviral mRNA Delivery Materials and Their Application as Vaccines for Melanoma Therapy

Abstract

Messenger RNA (mRNA) vaccines are promising platforms for cancer immunotherapy because of their potential to encode for a variety of tumor antigens, high tolerability, and capacity to induce strong antitumor immune responses. However, the clinical translation of mRNA cancer vaccines can be hindered by the inefficient delivery of mRNA in vivo. In this review, we provide an overview of mRNA cancer vaccines by discussing their utility in treating melanoma. Specifically, we begin our review by describing the barriers that can impede mRNA delivery to target cells. We then review native mRNA structure and discuss various modification methods shown to enhance mRNA stability and transfection. Next, we outline the advantages and challenges of three nonviral carrier platforms (lipid nanoparticles, polymeric nanoparticles, and lipopolyplexes) frequently used for mRNA delivery. Last, we summarize preclinical and clinical studies that have investigated nonviral mRNA vaccines for the treatment of melanoma. In writing this review, we aim to highlight innovative nonviral strategies designed to address mRNA delivery challenges while emphasizing the exciting potential of mRNA vaccines as next-generation therapies for the treatment of cancers.

Keywords: lipid nanoparticles; lipopolyplexes; mRNA vaccines; melanoma; polymeric nanoparticles.

Figure 1.

Cellular and Humoral Immune Response Induced by an mRNA Vaccine

Figure 2.

Mature mRNA structure and function and synthetic modification strategies used to optimize mRNA performance

Figure 3.

Examples of FDA-approved lipid nanoparticle components used in mRNA vaccines

Figure 4.

Representative examples of polymeric materials commonly used for mRNA delivery

Figure 5.

a) Schematic and cryogenic electron microscopy image of optimized mOVA LNP formulation. Reproduced with permission from reference (152), Copyright 2019 Springer Nature. b) Anti-tumor effect of CpG2018B and mRNA LNP combination therapy. Images (left) and weights (right) of tumors resected from mice treated with negative control (NC), CpG, LNP-based mRNA vaccine, or CpG2018B combined with LNP-based mRNA vaccine. Reproduced with permission from reference (154), Copyright 2021 Dove Medical Press Limited. c) Tumor rechallenging with IV injection of B16F10-OVA cells in untreated (UT) and surviving mice. The surviving mice were previously treated with the mRNA vaccine alone or in combination with anti-PD-1 therapy. Reproduced with permission from reference (157), Copyright 2022 PNAS. d) Tumor size and survival curve of mice treated with LNPs encapsulating multiple cytokine mRNAs. Reproduced with permission from reference (158), Copyright 2022 Elsevier.

Figure 6.

a) Graphical overview of F-PEI mRNA vaccine preparation (top) and tumor volumes and survival curves of mice bearing B16-OVA tumors in different treatment groups (bottom). Reproduced with permission from reference (160), Copyright 2022 Elsevier. b) Synthesis of lipid-like materials from PAMAM dendrimers (top) and B16-OVA tumor volumes from mice treated with OVA mRNA LNPs for therapeutic (bottom left) and prophylactic (bottom right) purposes. Reproduced with permission from reference (161), Copyright 2021 PNAS. c) Schematic of lipopolyplex mRNA vaccine (top) and number of tumor nodules in the lungs following treatment with lipopolyplex mRNA vaccine (LPP/OVA) in B16-OVA melanoma lung metastasis model (bottom). Reproduced with permission from reference (169), Copyright 2017 Elsevier. d) Vaccination schedule and tumor growth curve of B16-OVA inoculated mice following treatment with a lipopolyplex vaccine carrying either unmodified or N1-methylpseudouridine (N1mΨ) modified mRNA. Reproduced with permission from reference (170), Copyright 2018 American Chemical Society.