Rare genetic diseases, also known as orphan diseases, are mostly caused by single gene defects [[1], [2], [3]]. Although each rare genetic disease is characterized by its low prevalence in the population, over 7000 rare diseases have been identified globally, collectively affecting more than 350 million people [4,5]. These diseases are severely debilitating and often drastically reduce life expectancy due to the lack of effective treatments, imposing a significant burden on patients worldwide [6,7]. The late diagnosis, insufficient research and development due to their low prevalence make treating rare genetic diseases remain a significant challenge [8,9]. Gene therapy has been studied to treat genetic diseases by aiming to correct genetic defects. However, it has faced setbacks due to some inherent limitations of viral vector-based delivery systems, such as strong immunogenicity, the risk of genomic integration, limited carrying capacity, difficulty in regulating gene expression, and complex production processes [[10], [11], [12], [13]]. Therefore, there is an urgent need to develop more advanced personalized medicines capable of safely and durably correcting disease-causing genetic defects.

Currently, strategies for treating rare genetic diseases include dietary control, organ transplantation, protein replacement therapy, small molecule chaperones, gene therapy (lentiviral, adeno-associated, adenoviral vectors) and gene editing [14](Fig. 1). However, these approaches have limitations. Dietary control often only provides limited disease alleviation, and patient compliance can be challenging. Organ transplantation can address the underlying cause of disease, but is hampered by difficulties in finding a suitable donor, high costs, and the need for lifelong immunosuppressive therapy. Although enzyme replacement therapy (ERT) is common, it is ineffective for mutations that require the enzyme to function within cellular compartments like the mitochondria. Additionally, long-term use of recombinant enzymes can lead to resistance. In cystic fibrosis (CF), researchers have developed four cystic fibrosis transmembrane conductance regulator (CFTR) modulators (Elexacaftor, Tezacaftor, Ivacaftor, and Lumacaftor) that can enhance CFTR protein function, increase chloride permeability, improve mucociliary clearance, and lung function. However, these drugs are only effective for specific F508del mutations [15]. To date, nine gene therapy products have been approved for rare diseases, half of which target hematologic disorders, including Roctavian (hemophilia A), Hemgenix (hemophilia B), Zynteglo (β-thalassemia), and Lyfgenia (Sickle cell disease, SCD). These gene therapies primarily use viral vectors for delivery, but challenges remain due to limitations of viral vector delivery systems (e.g., high immunogenicity, presence of pre-existing antibodies, risks of genomic integration, limited cargo capacity, difficulty regulating transgene expression, complex quality control and manufacturing processes, etc. [[10], [11], [12], [13]]. Another approach is gene editing, which is widely investigated for treating rare genetic diseases. Recently, the gene editing drug “CASGEVY”, based on the Exagamglogene Autotemcel (Exa-cel) platform, was approved by the Medicines and Healthcare products Regulatory Agency, Food and Drug Administration (FDA) and European Commission for treating SCD and transfusion-dependent β-thalassemia. However, this is still limited to editing cells ex vivo before infusing them back into the patient, while in vivo editing has not yet achieved a breakthrough. Therefore, therapeutic modalities for rare genetic diseases still need to be developed to provide more options for patients.

In recent years, mRNA therapy has emerged as a promising approach in genetic disease treatment with several advantages, including biocompatibility, precise dosing, transient expression, and minimal risk of genomic integration [[16], [17], [18], [19]]. Chemical modifications of mRNA can potently reduce immunogenicity while increasing protein production, overcoming key limitations of previous nucleic acid therapies. Additionally, the modular design and mature manufacturing processes of mRNA therapies enable the rapid development of customized treatments for individual patients, which is crucial for heterogeneous rare genetic diseases. More importantly, mRNA therapy can safely restore missing or defective proteins by transient expression without changing genomic sequences, thus correcting underlying genetic defects while avoiding safety concerns from viral vector-mediated gene therapy like uncontrolled gene expression [[16], [17], [18], [19]]. Moreover, recent innovations in nanoparticle delivery systems, like LNPs, have enhanced mRNA stability and enabled efficient targeting to disease-relevant cells and tissues [[20], [21], [22], [23], [24]]. These characteristics make mRNA therapies an attractive option for genetic diseases previously considered difficult to treat or manage. Recent studies have demonstrated significant promise for mRNA therapy in rare genetic diseases, including glycogen storage disease (GSD) (NCT05095727, NCT04990388), propionic acidemia (PA) (NCT04159103, NCT05130437), ornithine transcarbamylase deficiency (OTCD) (NCT04442347, NCT05526066, NCT03767270), methylmalonic acidemia (MMA) (NCT04899310), CF (NCT05668741), and familial hypercholesterolemia (FH) (NCT05043181). Besides these studies reported favorable treatment outcomes, clinical trials are actively underway. Ongoing advancements in delivery materials and mRNA molecular design strategies will also continue to improve the clinical applications of mRNA therapy.

Given the current lack of effective treatments for most rare genetic diseases, the importance of accelerating research into mRNA therapy cannot be overstated. This review focuses on the application of mRNA therapy in rare genetic diseases, aiming to shed light on the potential of mRNA therapy and provide hope to individuals and families affected by these diseases. Generally, we explore mRNA therapy development, mRNA molecular design, and various mRNA delivery systems. Furthermore, we highlight their research progress in rare genetic diseases based on protein replacement and gene editing. We also summarize current research progress in applying mRNA therapy to rare genetic diseases and emphasize the challenges and future prospects of this revolutionary approach. We also encourage more researchers to join the field, address ongoing scientific and clinical challenges, and expedite the clinical adoption of mRNA therapy.