It is time to thoroughly evaluate the risks of mRNA drug and vaccine toxicity

Abstract

The mRNA formulations with lipid nanoparticle (LNP) delivery represent a transformative biotechnology that has demonstrated boundless potential during the global COVID-19 pandemic. Despite generally tolerable after used in billions of vaccine recipients, some toxicity cases have been reported, which presents challenges due to widespread application of mRNA vaccines. In our view, strategies to mitigate the toxicity risks associated with mRNA drugs, are crucial for ensuring the safety and efficacy of these therapies. The comprehensive introduction of LNP structural components, production methods, administration routes, and the proteins produced from mRNA formulations provides valuable insights into addressing potential toxicity concerns. However, it is important to acknowledge that throughout the entire mRNA therapeutic process, there are inherent toxicity risks that need to be carefully managed. These risks could pose a considerable challenge for the broad adoption of mRNA vaccines and other mRNA-based therapies (Figure 1).

The primary objective of this perspective is to explore strategies for reducing the toxicity risks associated with mRNA drugs and vaccines, including improving delivery systems, adjusting dosage and timing, and employing auxiliary molecules. To address these issues, in-depth research on the potential toxicity of mRNA vaccines are necessary, including a more comprehensive evaluation of their long-term effects in animal models and humans.

Furthermore, utilizing induced pluripotent stem cell, organoids, spheroids, and microfluidic technologies can enhance the physiological relevance and data diversity of in vitro studies. The authors emphasize new trends in in vitro modeling, including high-throughput models and machine learning algorithms. They highlight the potential of organ-on-chip technology, which recreates 3D tissues mirroring specific organs' phenotype, functionality, and transcriptomic profiles. These techniques allow the emulation of pathological physiological conditions in vitro and enable the tracking of molecular pathways associated with drug toxicity.

We emphasize the importance of developing physiologically relevant in vitro models to mitigate risks in the preclinical development process. The ethical considerations, limited availability of animals, and FDA's reliance on in vitro data all raise concerns regarding the safety of mRNA vaccines, as well as the accuracy of physiologically relevant in vitro models. Strengthening safety assessment is crucial, necessitating comprehensive studies, monitoring of diverse populations, and establishment of robust surveillance systems to investigate adverse events following mRNA vaccination.

Frontier areas in mRNA drug delivery technology are yet to be explored, presenting new possibilities for mitigating the toxicity risks linked to mRNA drugs and vaccines. Microneedles responsive to mechanical, temperature, electrical, optical, magnetic, pH, and various biomarkers have become a hotspot in intelligent delivery systems.¹ Nano-robots can manufacture small-scale micro/nanodevices using biocompatible materials, enabling the transportation of drugs, diagnostic reagents, and even living cells and microorganisms.² In recent years, there has been notable advancement in biomimetic drug delivery systems, with key carriers encompassing bacteria, viruses, cells, extracellular vesicles, and various vesicles mimicking other biological particles and structures.^{3, 4}

Meanwhile, the complex production procedures of advanced drug delivery systems with novel materials or formulations, protected by patents, hinder replication postexpiration. Limited disclosure of experimental procedures adds to this complexity. Generic formulation development primarily remains at the lab stage. Breaking multinational monopolies on high-end formulations and enhancing safety verification mechanisms are crucial for vaccine sector growth and enable the faster development of mRNA therapeutics.

The timely review⁵ provides valuable insights into strategies for reducing the toxicity risks associated with mRNA drugs and vaccines. Safety development of mRNA-based drugs and vaccines requires multidisciplinary approaches, combining advanced in vitro toxicity screening methods, omics datasets for early risk identification, and close monitoring of the evolving development process of mRNA formulations. As mRNA therapy is a budding technology, relevant authorities must conduct thorough evaluations of mRNA vaccines by objectively assessing both mRNA's potential risks and benefits, while ensuring comprehensive risk communication and informed consent with vaccine recipients. Concurrently, there is a pressing need to bolster public education and awareness efforts to enhance understanding of the safety of mRNA vaccines and mitigate unwarranted panic and misconceptions. Reinforcing public education initiatives can foster greater awareness regarding the safety profile of mRNA vaccines, minimize unnecessary anxiety and confusion, and ultimately accelerate the research and production of mRNA drugs.

Ruoyang Zhao and Jun Guo wrote the manuscript and drew the figure. Min Wu initiated, supervised and revised the manuscript writing. All authors have read and approved the final manuscript.

The authors declare no conflict of interest.

Not applicable.