Chemically Synthesized Minimal mRNA (CmRNA) represents a significant breakthrough with inherent stability and enhanced translational efficiency, free from untranslated regions and polyadenylation ¹. Our recommended approach involves encapsulation CmRNA within Lipid-Polymer Hybrid Nanoparticles (LPPs), leveraging their controlled release capabilities and superior pharmacokinetics ^2,3. This novel strategy holds promise for future advancements in mRNA therapeutics.

Our perspective review paper is inspired by robustly validated articles and our own expertise. This paper meticulously details the distinctive attributes of CmRNA, emphasizing its cap-independent translation pathway, precisely tailored design for efficient translation, and strategic omission of non-essential elements such as poly-A tails and UTRs ^1,4,5. The inherent advantages of CmRNA, including robust stability and efficient immune system stimulation, position it as a potent instrument in the toolkit of personalized and targeted cancer therapy.

• Inspiration

Our envisioned prospective review paper stems from a commitment to exploring and synthesizing validated advancements in cancer immunotherapy. Drawing inspiration from articles in the field and combining it with our teams’ expertise, this paper aims to present a novel perspective. Focusing on the marriage of CmRNA and LPPs, we aspire to create an overview of the current state of the art with a forward-looking perspective, proposing innovative concepts that could shape the future of cancer treatment. Our perspective paper could serve as a guiding beacon in the dynamic landscape of cancer immunotherapy research ^6,7.

• Advancements and Scientific Significance

The exploration of CmRNA in cancer immunotherapy marks a groundbreaking and forward-thinking approach, presenting a novel idea with transformative potential. The distinctive advantages of CmRNA over conventional mRNA vaccination methods, such as in vitro transcribed mRNA (IVT-mRNA) and Circular RNAs (circRNAs), positions this research at the forefront of scientific inquiry ^8,9. The scientific significance of CmRNA lies in its ability to not just address, but surpass the limitations of traditional methods, promising a future where precision, stability, translatability, and targeted delivery redefine the landscape of mRNA-based therapeutics ^10,11. Moreover, the integration of LPPs as a delivery system introduces an innovative solution for targeted delivery, enhancing the specificity of CmRNA in optimizing immune responses against cancer ^15,16.

The meticulous examination of CmRNA-induced immune responses and its precision in tailoring cancer immunotherapy to individual patients showcase the immense potential of this idea. This research doesn't just address current challenges; it offers a promising avenue for a paradigm shift in mRNA-based therapeutic approaches ¹⁷. The combination of CmRNA and LPPs, therefore, represents a prospective and impactful direction for advancing cancer immunotherapy.

• The Future

As we look forward, we anticipate a paradigm shift in clinical practice, wherein the precision of CmRNA design seamlessly integrates with sophisticated LPP delivery systems ^18,19. This harmonious synergy aspires not only to overcome existing challenges, but also to establish new benchmarks in therapeutic efficacy, safety, and ultimately, in improving patient outcomes. Our vision for CmRNA-LPPs vaccination is centered around key advancements that promise to redefine personalized cancer immunotherapy:

• Optimizing Vaccine Design: The future involves a relentless pursuit of refining vaccine design. This includes tailoring CmRNA sequences to individual neoantigens, optimizing codon usage, and exploring further sequence The goal is to fine-tune the immune response, ensuring that personalized vaccines elicit robust and durable protection against cancer while minimizing off-target effects.
• Advanced Delivery Systems: LPPs, as carriers of CmRNA, offer opportunities as advanced delivery systems. Future research will optimize LPP properties, exploring novel excipients, and engineering smart nanocarriers for targeted and sustained release. This trajectory aims to enhance the pharmacokinetics of CmRNA, allowing for precise control over vaccine distribution, uptake, and immune activation ²⁰.
• Safety Assessments for Clinical Trials: Safety remains paramount as we progress. Future endeavors will address safety concerns associated with CmRNA-based vaccines. Rigorous preclinical studies and comprehensive toxicity assessments will pave the way for seamless transitions to clinical trials. The goal is to not only demonstrate the efficacy but also to establish a safety profile that instills confidence in clinicians and patients.
• Shaping Precision Medicine: Definingly, the success of CmRNA-LPP vaccines extends beyond cancer immunotherapy. This model of vaccination may serve as a blueprint for precision medicine across various therapeutic domains. Tailoring therapeutic interventions to individual genetic profiles, leveraging mRNA technologies, and employing advanced delivery systems can potentially revolutionize treatment strategies for a spectrum of diseases beyond oncology ⁶.
• Global Collaborations and Accessibility: Collaboration and investment on the CmRNA-LPP vaccine is a cornerstone for the future. Fostering global collaborations among clinicians, researchers, and industry to pool diverse expertise, and establishing standardized protocols are on the agenda. Simultaneously, efforts will ensure accessibility, making these cutting-edge therapies available to diverse populations worldwide. This commitment aligns with the goal of advancing global health through inclusive and collaborative initiatives.

• Summary

Our perspective article introduces a transformative vision for personalized cancer treatment through CmRNA-LPPs, marking a paradigm shift in mRNA therapy. With concise CmRNA design surpassing IVT-mRNA, we propose improved stability, efficient translation, and superior immunogenicity. LPP encapsulation amplifies these attributes, promising controlled release, targeted delivery, and enhanced immune stimulation. This forward-looking idea is not just a scientific endeavor but a cornerstone for ongoing and prospective research. Our ongoing studies rely on the potential of CmRNA-LPPs to redefine precision medicine, ushering in an era where tailored therapeutics break through conventional treatment boundaries.

• About Authors

Professor Chantal Pichon serves as the corresponding author for this paper, while Professor Oya Tagit and Dr. Saber Imani act as co-first authors. Chantal Pichon has an established professorship at the University of Orleans (France) and an innovation chair at the Institut Universitaire de France (Paris), C. Pichon is conducting interdisciplinary projects based on chemistry and molecular and cell biology with a crosstalk between basic and applied researches. Her main research activities are dedicated to the use of nucleic acids as therapeutics, especially messenger RNAs as vaccines and therapeutics. Her lab is developing innovative formulations for their delivery for various applications: mucosal vaccination, imune cell-based therapies and protein replacement therapy. She is also developping a challeging project to build an economically sustainable biotechnology process for production of high-quality mRNA therapeutics opening their use in different applications. Saber Imani, an independent Assistant Professor at Shulan International Medical College, Zhejiang Shuren University, Hangzhou, China, heads a dedicated research lab specializing in "mRNA Cancer Vaccine" and "Translational Oncology." His group is deeply committed to advancing the field of mRNA-based cancer vaccines and unraveling the complexities of translational oncogenesis, thereby contributing to a profound understanding of cancer development and identifying potential therapeutic targets. Professor Oya Tagit, a full professor and head of the Biointerfaces group at the Institute of Chemistry and Bioanalytics at the University of Applied Sciences Northwestern Switzerland (FHNW), brings extensive expertise to the bench-to-bedside development of nanoparticles for disease diagnosis, monitoring, and treatment, with a particular emphasis on cancer. Her interdisciplinary research group combines expertise in polymer chemistry, nanomaterials, and cell biology to develop novel nanotherapeutic approaches via designing, characterizing, and scaling up the manufacturing of nanoparticles loaded with various (bio)therapeutics.

During the past decade, the collaborative efforts of these distinguished researchers have spanned various centers, fostering a dynamic team poised for future collaborations on CmRNA. They welcome engagement from the scientific community, seeking to enhance CmRNA-LPPs and contribute valuable insights. Feedback and suggestions from users are encouraged, playing a pivotal role in shaping the direction of our ongoing development endeavors.

• References

1. Abe, N., et al. Complete Chemical Synthesis of Minimal Messenger RNA by Efficient Chemical Capping Reaction. ACS Chem Biol 17, 1308-1314 (2022).
2. Gong, C., et al. Regulating the immunosuppressive tumor microenvironment to enhance breast cancer immunotherapy using pH-responsive hybrid membrane-coated nanoparticles. J Nanobiotechnology 19, 58 (2021).
3. Meyer, R.A., Hussmann, G.P., Peterson, N.C., Santos, J.L. & Tuesca, A.D. A scalable and robust cationic lipid/polymer hybrid nanoparticle platform for mRNA delivery. Int J Pharm 611, 121314 (2022).
4. Nagata, S., et al. Synthesis and biological activity of artificial mRNA prepared with novel phosphorylating reagents. Nucleic Acids Res 38, 7845-7857 (2010).
5. Shatsky, I.N., Terenin, I.M., Smirnova, V.V. & Andreev, D.E. Cap-Independent Translation: What's in a Name? Trends Biochem Sci 43, 882-895 (2018).
6. Wadhwa, A., Aljabbari, A., Lokras, A., Foged, C. & Thakur, A. Opportunities and Challenges in the Delivery of mRNA-based Vaccines. Pharmaceutics 12(2020).
7. Zhu, X. & Li, S. Nanomaterials in tumor immunotherapy: new strategies and challenges. Mol Cancer 22, 94 (2023).
8. Li, H., et al. Circular RNA cancer vaccines drive immunity in hard-to-treat malignancies. Theranostics 12, 6422-6436 (2022).
9. Kristensen, L.S., et al. The biogenesis, biology and characterization of circular RNAs. Nat Rev Genet 20, 675-691 (2019).
10. Santer, L., Bar, C. & Thum, T. Circular RNAs: A Novel Class of Functional RNA Molecules with a Therapeutic Perspective. Mol Ther 27, 1350-1363 (2019).
11. Sandalova, T., Sala, B.M. & Achour, A. Structural aspects of chemical modifications in the MHC-restricted immunopeptidome; Implications for immune recognition. Front Chem 10, 861609 (2022).
12. Andries, O., et al. N(1)-methylpseudouridine-incorporated mRNA outperforms pseudouridine-incorporated mRNA by providing enhanced protein expression and reduced immunogenicity in mammalian cell lines and mice. J Control Release 217, 337-344 (2015).
13. Gao, M., Zhang, Q., Feng, X.H. & Liu, J. Synthetic modified messenger RNA for therapeutic applications. Acta Biomater 131, 1-15 (2021).
14. Pastor, F., et al. An RNA toolbox for cancer immunotherapy. Nat Rev Drug Discov 17, 751-767 (2018).
15. Fang, R.H., et al. Large-scale synthesis of lipid-polymer hybrid nanoparticles using a multi-inlet vortex reactor. Langmuir 28, 13824-13829 (2012).
16. Mukherjee, A., et al. Lipid-polymer hybrid nanoparticles as a next-generation drug delivery platform: state of the art, emerging technologies, and perspectives. Int J Nanomedicine 14, 1937-1952 (2019).
17. Andretto, V., et al. Hybrid core-shell particles for mRNA systemic delivery. J Control Release 353, 1037-1049 (2023).
18. Huang, K.J., et al. Delivery of Circular mRNA via Degradable Lipid Nanoparticles against SARS-CoV-2 Delta Variant. bioRxiv (2022).
19. Gill, T., et al. Selective targeting of MYC mRNA by stabilized antisense oligonucleotides. Oncogene 40, 6527-6539 (2021).
20. Husseini, R.A., Abe, N., Hara, T., Abe, H. & Kogure, K. Use of Iontophoresis Technology for Transdermal Delivery of a Minimal mRNA Vaccine as a Potential Melanoma Therapeutic. Biol Pharm Bull 46, 301-308 (2023).