Better, Faster, Stronger: Accelerating mRNA-Based Immunotherapies With Nanocarriers

Abstract

Messenger ribonucleic acid (mRNA) therapeutics are attracting attention as promising tools in cancer immunotherapy due to their ability to leverage the in vivo expression of all known protein sequences. Even small amounts of mRNA can have a powerful effect on cancer vaccines by promoting the synthesis of tumor-specific antigens (TSA) or tumor-associated antigens (TAA) by antigen-presenting cells (APC). These antigens are then presented to T cells, eliciting strong antitumor immune stimulation. The potential of mRNA can be further enhanced by expressing immunomodulatory agents, such as cytokines, antibodies, and chimeric antigen receptors (CAR), enhancing tumor immunity. Recent research also explores mRNA-encoded tumor death inducers or tumor microenvironment (TME) modulators. Despite its promise, the clinical translation of mRNA-based anticancer strategies faces challenges, including inefficient targeted delivery in vivo, failure of endosomal escape, and inadequate intracellular mRNA release, resulting in poor transfection efficiencies. Inspired by the approval of lipid nanoparticle-loaded mRNA vaccines against coronavirus disease 2019 (COVID-19) and the encouraging outcomes of mRNA-based cancer therapies in trials, innovative nonviral nanotechnology delivery systems have been engineered. These aim to advance mRNA-based cancer immunotherapies from research to clinical application. This review summarizes recent preclinical and clinical progress in lipid and polymeric nanomedicines for delivering mRNA-encoded antitumor therapeutics, including cytokines and antibody-based immunotherapies, cancer vaccines, and CAR therapies. It also addresses advanced delivery systems for direct oncolysis or TME reprogramming and highlights key challenges in translating these therapies to clinical use, exploring future perspectives, including the role of artificial intelligence and machine learning in their development.

Keywords: cancer immunotherapy; mRNA‐based delivery systems; messenger RNA (mRNA) therapeutics; nanotechnology.

FIGURE 1

mRNA‐loaded nanocarrier engineering and cancer immunotherapy applications. By adjusting mRNA and nanocarrier properties, each mRNA‐encoded immunomodulator can be delivered and produced with the precise spatiotemporal control desired for its therapeutic effect. APC: antigen‐presenting cell; CAR: chimeric antigen receptor; M: macrophage; mRNA: messenger ribonucleic acid; NK: natural killer cell; TCR: T‐cell receptor; UTR: untranslated region.

FIGURE 2

In vivo antitumoral responses induced by NP‐delivered mRNA‐encoded cytokines and antibodies. mRNA is delivered into target cells via NP endocytosis. During internalization, the acidic pH triggers the endosomal escape effect of the ionizable lipids by fusing the NP with the endosome membrane, releasing the mRNA into the cell cytoplasm. Once in the cytoplasm, mRNA is translated into the encoded proteins, which undergo posttranslation modifications to acquire the proper folding and chemical structure. Following their expression, mRNA‐encoded cytokines can induce potent antitumoral responses in both injected and non‐injected lesions through several immune mechanisms, including IFN‐γ level increase, T‐cell expansion and survival enhancement, stimulation of APC antigen presentation through immune cell activation or increased MHC molecule expression, and TME remodeling toward a T_H1 phenotype with higher immune infiltration ratios. Similarly, in vivo synthesized monoclonal antibodies (mAbs) and bispecific antibodies (bsAbs) may also generate pronounced antitumor responses. These responses include promoting an M1 proinflammatory TME, improving immune cell infiltration into the tumor, activating different immune cell subsets, inhibiting immune checkpoint interaction with their ligands, or bringing immune cells like T cells closer to cancer cells, thereby inducing targeted T cell‐dependent cytotoxicity. APC: antigen‐presenting cell; B7H3: B7 homolog 3 protein; bsAb: bispecific antibody; CCL: chemokine (C–C motif) ligand; CLDN6: claudin 6; DC: dendritic cell; EpCAM: epithelial cellular adhesion molecule; IFN‐γ: interferon‐γ; IL: interleukin; LNP: lipid nanoparticle; mAb: monoclonal antibody; NK: natural killer cell; NKT: natural killer T cell; PD‐1: programmed cell death protein‐1; PD‐L1: programmed cell death‐ligand 1; TME: tumor microenvironment.

FIGURE 3

Cancer mRNA vaccine antigen composition and in vivo DC‐targeted mRNA vaccine‐induced antitumor response mechanisms. Each mRNA‐loaded nanocarrier vaccine can encode one or multiple TAA and/or TSA based on the antigen landscape of the patient's tumor. Due to the versatility of mRNA‐loaded nanocarriers, personalized cancer vaccines can be tailored using tumor neoantigen screening techniques such as NGS and LC/MS coupled with antigen selection by immunogenicity prediction algorithms. Upon administration, DC‐targeted mRNA‐loaded nanocarriers are taken up by local DC and accumulate in secondary lymph organs. Following mRNA cytoplasmic release and translation, DC mature and present the mRNA‐encoded antigens via MHC class I, MHC class II, and free antigen secretion. These DC activate T and B cells in secondary lymph organs to induce a broad adaptive immune response. The activated immune cells subsequently traffic to and infiltrate the tumor, inducing tumor cell death and potentially initiating the antitumor immunity cycle through TME remodeling and epitope spreading. CD: cluster of differentiation; CMVpp65: cytomegalovirus matrix protein pp65; DC: dendritic cell; LC/MS: liquid chromatography‐mass spectrometry; MAGE‐A3: melanoma‐associated antigen 3; MHC: major histocompatibility complex; NGS: next‐generation sequencing; NP: nanoparticle; NY‐ESO‐1: New York esophageal squamous cell carcinoma 1; PSA: prostate‐specific antigen; PSCA: prostate stem cell antigen; PSMA: prostate‐specific membrane antigen; STEAP1: six transmembrane epithelial antigen of the prostate 1; TAA: tumor‐associated antigen; TME: tumor microenvironment; TSA: tumor‐specific antigen; UTR: untranslated region; WT1: Wilm's tumor 1.

FIGURE 4

CAR‐encoded mRNA‐loaded nanocarrier engineering and CAR‐T cell generation methods. 4‐1BB: tumor necrosis factor ligand superfamily member 9; CART: charge‐altering releasable transporters; CAR‐T: chimeric antigen receptor‐T cell; CD: cluster of differentiation; DARPin: designed ankyrin repeat proteins; scFv: single‐chain variable fragment; SORT lipid: selective organ‐targeting lipid; UTR: untranslated region.

FIGURE 5

Schematic representation of mRNA‐loaded NP that prompts the synthesis of toxic intracellular proteins, forcing tumor cells to self‐destruction. Moreover, autophagy‐mediated tumor cell death can also trigger ICD, which promotes the release of cytokines and the secretion of TSA and DAMP, resulting in immune cell recruitment that contributes to TME reprogramming. The polarization of a “cold” and immunosuppressive TME to an immunogenic “hot” is mediated by (1) increased levels of tumor‐infiltrating antitumor cells, including CD8⁺ and CD4⁺ T, and NK cells; (2) TAM polarization toward the M1‐type antitumor phenotype; (3) enhanced expression of proinflammatory cytokines (TNF–α and IFN‐γ); and (4) downregulation of immunosuppression‐related Treg and MDSC levels. DAMP: damage‐associated molecular patterns; ICD: immunogenic cell death; IFN: interferon; MDSC: myeloid‐derived suppressor cells; mRNA: messenger ribonucleic acid; NK: natural killer; NP: nanoparticle; TAM: tumor‐associated macrophages; TME: tumor microenvironment; TNF: tumor necrosis factor; Treg: regulatory T cells; TSA: tumor‐specific antigens.