Engineered MSC-Exosomes Delivering miRNAs for Respiratory Disease Diagnostics and Therapy: Opportunities and...

Respiratory diseases pose a severe threat to global health, with notable limitations in current diagnosis and treatment, such as insufficient sensitivity of diagnostic tools and a lack of effective targeted therapies. Due to their highly efficient information transmission capabilities and excellent safety profile, exosomes carrying non-coding RNA, particularly microRNA (miRNA), are increasingly attracting attention. Compared with free miRNAs, exosomes can protect miRNAs from nuclease degradation, prolong their circulation time in the body, thereby improving the stability and bioavailability of miRNAs. At the same time, they can also address the major bottleneck in the clinical application of miRNAs, including low in vivo delivery efficiency, poor stability, lack of targeting specificity, and off-target effects. Increasing evidence indicate that miRNAs play a significant role in respiratory diseases, including targeting multiple signaling pathways, regulating inflammation and oxidative stress, influencing tumor growth and apoptosis, and participating in tissue damage and repair, thus holding promising prospects for diagnosis and treatment in respiratory diseases. MSC-derived exosomes exhibit low tumorigenic risk because they originate from adult stem cells with limited differentiation ability, have low immunogenicity, and do not highly express major histocompatibility complex class II (MHC-II) molecules, making them suitable for allogeneic use. To enhance the therapeutic efficacy and specificity of exosomes in respiratory diseases, engineering modifications of MSC-exosomes (MSC-exos) are crucial. Current methods for engineering MSC-exos primarily include cargo loading and surface modification to improve therapeutic efficacy and targeting specificity. Through these engineering methods, more precise miRNA delivery can be achieved, reducing the side effects of traditional treatments and improving treatment efficacy. Although MSC-exos demonstrate significant potential in treating respiratory diseases, their clinical translation is hindered by critical hurdles, including individual differences in therapeutic efficacy, insufficient miRNA targeting specificity, challenges in large-scale production, and potential immunogenicity risks. To accelerate clinical application, future research should prioritize optimizing engineered targeting strategies (eg, precision surface modification), enhancing large-scale preparation efficiency of functional MSC-exos, and validating their long-term safety and efficacy in multi-center studies. At present, the good manufacturing practice (GMP) production process of MSC-exos has been established. Early clinical trials (Phase I/II) have shown its potential in respiratory diseases such as pulmonary fibrosis without serious adverse reactions. However, it has not yet been approved for clinical transformation and still faces challenges such as large-scale targeting and safety. Overall, MSC-exos carrying miRNAs show great promise in the treatment of respiratory diseases, but their true clinical application still requires more systematic research and validation.