Nebulized mesenchymal stem cell-derived exosomes encapsulating interferon-α2b: A synergistic strategy for targeted treatment of severe viral

Title : Nebulized mesenchymal stem cell-derived exosomes encapsulating interferon-α2b: A synergistic strategy for targeted treatment of severe viral

Abstract:

Background: Severe viral pneumonias, particularly those caused by influenza A virus, respiratory syncytial virus (RSV), and emerging coronaviruses, continue to pose formidable challenges to global public health. While Interferon-alpha (IFN-α) remains a cornerstone of antiviral therapy due to its potent induction of antiviral states in host cells, its clinical utility via traditional delivery routes is severely constrained. Systemic administration often triggers significant adverse effects, including bone marrow suppression and neurotoxicity. Conversely, direct nebulized inhalation of naked IFN-α proteins is hindered by rapid proteolytic degradation in the lung microenvironment, poor retention in deep alveolar tissues, and loss of bioactivity during the high-shear nebulization process. There is an urgent clinical need for a delivery system that ensures both stability and localized therapeutic concentration.

Methods: In this study, we developed Exo-Aero α, a translational biomimetic nano-platform designed to overcome these barriers. Mesenchymal stem cell-derived exosomes (MSC-Exos) were isolated from P3 generation cells via ultracentrifugation and characterized as the primary delivery vehicle. Recombinant human IFN-α2b was encapsulated into the MSC-Exos using a proprietary physical-chemical loading and micro-extrusion protocol, optimizing the "Target-Treat-Repair" trinity logic. To facilitate large-scale distribution and clinical application, the formulation was engineered into a stable lyophilized powder using a specialized vacuum-freeze-drying process (10Pa/-50°C). The physicochemical properties, including particle size distribution (NTA), morphology (TEM), and post-nebulization bioactivity, were rigorously validated. Therapeutic efficacy was evaluated in a murine model subjected to a lethal-dose H1N1 viral challenge.

Results: The Exo-Aero α platform exhibited a highly uniform and stable particle size of 85.2 ± 21.6 nm, optimized for deep lung penetration. Post-nebulization analysis confirmed that the exosomal lipid bilayer provided robust physical shielding, maintaining over 95% of IFN-α2b biological activity. In vivo results demonstrated that the synergistic Exo-Aero α group achieved a remarkable 100% survival rate against lethal-dose H1N1 infection, significantly outperforming the IFN-α2b monotherapy group (32% survival) and the MSC-Exos group (60% survival). Mechanistic investigations revealed a profound "1+1>2" synergistic effect: IFN-α2b effectively suppressed viral replication via the JAK-STAT signaling pathway, while the MSC-Exos functioned as a potent immunomodulator, suppressing the pro-inflammatory "cytokine storm" and promoting the regeneration of damaged alveolar epithelial cells.

Conclusion: Exo-Aero α successfully bridges the gap between potent antiviral efficacy and lung tissue repair. By integrating endogenous exosomal carriers with stabilized cytokines, this platform provides a safe, scalable, and highly effective strategy for the management of severe respiratory infections. Our findings support the further clinical translation of this platform as a next-generation therapeutic for acute lung injury and infectious diseases.

Biography:

Dr. Yan Liu is a distinguished Senior Research Engineer and clinical translation expert at the National Center for Translational Medicine (Shanghai), Ruijin Hospital. She earned her Ph.D. from the Shanghai Institute of Pharmaceutical Industry (SIPI) in 2009 and subsequently spent over a decade at SIPI’s Gene Engineering Drug Innovation Center. In 2022, she expanded her international academic vision as a visiting scholar at the University of São Paulo, Brazil, before joining Ruijin Hospital to spearhead biopharmaceutical R&D and clinical translation.

With nearly 15 years of experience in the "closed-loop" development of novel biopharmaceuticals, Dr. Liu’s expertise encompasses pharmacodynamics, molecular mechanisms, and complex clinical research management. Her career is marked by significant regulatory achievements, including obtaining two clinical approvals (INDs) for Class I New Drugs. She has been a principal investigator or key member in numerous prestigious national programs, including the National 863 Program, the National Major New Drug Discovery Projects (spanning the 12th and 13th Five-Year Plans), and multiple Ministry of Science and Technology (MOST) Major Projects.

Dr. Liu has a prolific academic record with 16 peer-reviewed research papers, including 9 as first or co-first author in high-impact SCI journals. Her innovation is further evidenced by 13 authorized invention patents. Her research focus remains steadfast on anti-infective drug development and therapeutic mechanisms. Notably, her pioneering work on the combination of TFF2 and Type I Interferon as a potent candidate for COVID-19—demonstrating superior safety and efficacy in clinical trials—was published as back-to-back co-first author papers in The Lancet EClinicalMedicine. 

Following these breakthroughs, her team optimized the design to create a recombinant TFF2-IFN fusion protein, which simultaneously inhibits viral replication, modulates immune responses, and repairs respiratory mucosa—a dual-function mechanism published in Frontiers in Pharmacology (2022). Her current leadership of the Exo-Aero α project builds upon this established excellence, aiming to revolutionize the treatment of severe respiratory infections through exosome-based targeted delivery.