mRNA therapeutics is a novel and promising approach for the treatment of various diseases, especially cancer. By delivering synthetic mRNA molecules into the cells, mRNA therapeutics can induce the expression of desired proteins, such as antigens, antibodies, enzymes, or cytokines, to modulate the immune system, correct genetic defects, or enhance cellular functions. The design and delivery of mRNA molecules is a crucial step for the success of mRNA therapeutics, especially for cancer immunotherapy. However, there are many challenges and limitations that need to be overcome, such as low stability, poor translation efficiency, and the innate immunogenicity of mRNA molecules. Therefore, various strategies and methods have been developed to enhance the performance and safety of mRNA therapeutics, such as mRNA modification, nanoparticle formulation, and delivery optimization.
mRNA modification is a strategy to enhance the stability and translation efficiency of mRNA molecules, which are essential for the expression and function of the desired proteins. mRNA molecules are prone to degradation by various enzymes, such as RNases, in the extracellular and intracellular environments. Moreover, mRNA molecules have low affinity and accessibility to the ribosomes, which are the sites of protein synthesis. Therefore, mRNA modification aims to protect and improve the mRNA molecules by introducing chemical or structural changes to their components.
One of the main components of modification is the mRNA 5' cap, which is a modified nucleotide that is attached to the 5' end of the mRNA molecule. The 5' cap serves as a recognition signal for the initiation of translation, and also protects the mRNA from 5' exonucleases. Another component of mRNA modification is the untranslated regions (UTRs), which are the sequences at the 5' and 3' ends of the mRNA that do not encode any protein. The UTRs regulate the stability, localization, and translation of the mRNA by interacting with various factors, such as RNA-binding proteins and microRNAs. A third component of mRNA modification is codon optimization, which is the process of altering the codon usage of the mRNA to match the preferred codons of the host cell. Codon optimization can increase the translation efficiency and accuracy of the mRNA by reducing the frequency of rare codons, which can cause ribosomal stalling or misincorporation of amino acids. A fourth component of mRNA modification is the poly(A) tail, which is a long sequence of adenine nucleotides that is added to the 3' end of the mRNA molecule. The poly(A) tail enhances the stability and translation of the mRNA by preventing 3' exonucleases and facilitating the interaction with poly(A)-binding proteins. A fifth component of mRNA modification is the nucleoside modification, which is the substitution of the natural nucleosides (A, U, C, and G) with modified nucleosides, such as pseudouridine (Ψ), N1-methylpseudouridine (m1Ψ), or 5-methylcytidine (m5C). Nucleoside modification can improve the stability and translation of the mRNA by reducing the immunogenicity and enhancing the folding of the mRNA.
Nanoparticle formulation is a strategy to protect and deliver mRNA molecules, which are vulnerable to degradation and clearance in the biological environment. Nanoparticles are small particles that have a size range of 1-100 nm and can encapsulate or associate with mRNA molecules to form nanocomplexes. Nanoparticles can shield the mRNA from enzymatic and chemical degradation and enhance the cellular uptake and endosomal escape of the mRNA. Nanoparticles can also modulate the pharmacokinetics and biodistribution of mRNA and improve the safety and efficacy of mRNA therapeutics.
There are various types of nanoparticles that have been used for mRNA delivery, such as protein-mRNA complexes, lipid-based carriers, polymer-based carriers, and hybrid carriers. Protein-mRNA complex is a simple and biocompatible system that uses proteins, such as protamine or histone, to bind and condense mRNA molecules. Lipid-based carriers are the most widely used and clinically advanced system that uses lipids, such as cationic lipids or lipidoids, to form liposomes or lipid nanoparticles with mRNA. Polymer-based carriers are a versatile and tunable system that uses polymers, such as polyethylenimine or poly(lactic-co-glycolic acid), to form polyplexes or microparticles with mRNA. Hybrid carriers are a novel and multifunctional system that combines different materials, such as lipids and polymers, or nanoparticles and microneedles, to achieve synergistic effects for mRNA delivery.
Delivery optimization is a strategy to improve mRNA biodistribution and pharmacokinetics, which are critical for the therapeutic outcome and safety of mRNA therapeutics. Biodistribution refers to the spatial and temporal distribution of the mRNA in the body, and pharmacokinetics refers to the rate and extent of the mRNA absorption, distribution, metabolism, and excretion. Delivery optimization aims to enhance the target specificity and accumulation of the mRNA and reduce the off-target effects and toxicity of the mRNA.
There are various strategies and methods that have been used to optimize mRNA delivery, such as surface modification, targeting ligands, stimuli-responsive mechanisms, and co-delivery of adjuvants. Surface modification is a method to alter the surface properties of the nanoparticles, such as charge, hydrophilicity, and stealthiness, to improve the stability, circulation, and biocompatibility of the mRNA. Targeting ligands are molecules that can bind to specific receptors or antigens on the target cells or tissues, such as antibodies, aptamers, or peptides, to enhance the cellular uptake and specificity of the mRNA. Stimuli-responsive mechanisms are features that can respond to external or internal stimuli, such as light, temperature, pH, or enzymes, to trigger the release or activation of the mRNA. Co-delivery of adjuvants are substances that can enhance the immune response or modulate the immune environment, such as cytokines, toll-like receptor agonists, or checkpoint inhibitors, to improve the efficacy and safety of mRNA therapeutics.
Despite the remarkable progress and potential of mRNA therapeutics for cancer immunotherapy, there are still some current challenges and future directions that need to be addressed and explored in the field of mRNA design and delivery. Some of the current challenges include the optimization of the mRNA dose, duration, and frequency—the evaluation of the long-term safety and efficacy of mRNA therapeutics, the identification of the optimal combination and sequence of mRNA therapeutics with other modalities, such as chemotherapy, radiotherapy, or immunotherapy, and the development of personalized and precision mRNA therapeutics based on the molecular and immunological profiles of the patients and tumors. Some of the future directions include the development of new types of mRNA modification, nanoparticle formulation, and delivery optimization, the discovery of new targets and mechanisms for mRNA therapeutics, the integration of artificial intelligence and machine learning for mRNA design and delivery, and the translation of mRNA therapeutics from preclinical to clinical studies.
Creative Biolabs is a CRO dedicated to advancing mRNA therapy. We currently offer comprehensive services, including mRNA synthesis, mRNA modification, and mRNA drug optimization. We are your ideal one-stop partner for mRNA drug development.
References
