Development of a new therapy for ARDS based on the identification of miRNAs from stem cell-derived extracellular vesicles

Aina Areny Balagueró

Dr. Antonio Artigas Raventós and Dr. Daniel Closa Autet

Respiratory pathophysiology in the critical patient of the A8G3 group – Translational research in the Critical patient, at the Parc Taulí Research and Innovation Institute (I3PT)

Acute Respiratory Distress Syndrome (ARDS) is a serious and complex pathology that affects approximately 10% of patients admitted to intensive care units worldwide. Despite advances in clinical management and ventilatory support, there is currently no specific pharmacological treatment capable of restoring lung function and reducing associated mortality. This lack of effective therapies highlights the urgent need to develop new strategies that promote lung tissue regeneration and resolution of the dysregulated inflammatory response characteristic of ARDS. In this context, my doctoral thesis focuses on the development of an innovative therapy based on extracellular vesicles (EVs) derived from mesenchymal stem cells (MSCs) and on the identification of microRNAs (miRNAs) responsible for their immunomodulatory and regenerative effects. MSCs have shown high therapeutic potential in preclinical models of acute lung injury, but their clinical application is limited by safety, feasibility and reproducibility issues. The EVs secreted by these cells reproduce many of their beneficial effects without the risks associated with cell therapy, which positions them as a promising alternative. Through functional analyses and miRNA expression profiling, this research has identified three molecules --miR-297, miR-93-5p and let-7b-5p -- as key effectors of the therapeutic activity of EVs. These miRNAs act synergistically to modulate the inflammatory response and promote the regeneration of the alveolar epithelium, processes essential for the recovery of lung function. Based on these results, the development of a therapeutic formulation based on the combination of these miRNAs encapsulated in biodegradable nanocapsules for direct administration to the lung is proposed. The work includes the characterization of different formulations of poly(lactic-co-glycolic acid) (PLGA) nanocapsules, a polymer approved for clinical use, demonstrating their safety, stability and optimal biodistribution after pulmonary administration. This vehicle allows a local and controlled release of miRNAs in target cells, minimizing their systemic dispersion and enhancing their efficacy. This strategy represents a step forward towards a new generation of highly customizable “cell-free” therapies, with great potential for their transfer to the biomedical and pharmaceutical industry. The results of this thesis establish the basis for the development of an innovative therapeutic product for the treatment of ARDS and other pulmonary diseases with similar pathophysiological mechanisms, based on the use of selected miRNAs and their targeted release through nanoparticles. This research contributes directly to the objective of the PIONER Awards of promoting the translation of scientific knowledge into therapeutic solutions with real impact on health and society, with potential for transfer to the biomedical and industrial sectors.

The thesis proposes an innovative therapeutic strategy for Acute Respiratory Distress Syndrome (ARDS), a condition with high mortality and no effective targeted treatments. The approach is based on: Therapeutic Concept: Inhalable nanocapsules of PLGA (biodegradable polymer) loaded with a patented combination of microRNAs (miRNAs) with immunomodulatory and regenerative properties. Scientific Basis: miRNAs were identified from extracellular vesicles secreted by mesenchymal stem cells (MSCs) under inflammatory conditions, targeting key pathways for inflammation resolution and alveolar repair. Delivery System: Encapsulation in PLGA nanocapsules enhances stability, controls release, and enables direct pulmonary administration via inhalation, minimizing systemic effects. Clinical Translation: Collaboration with Aerogen Ltd. demonstrated efficient nebulization using clinically approved devices, supporting feasibility for integration into ICU ventilatory support routines. Impact: Clinical: Potential to reduce ICU stay, accelerate recovery, and decrease mortality and long-term sequelae. Economic: Significant cost savings by reducing hospitalization and rehabilitation needs. Commercial: High valorization potential due to patented miRNA combination, regulatory-accepted delivery system, and compatibility with existing medical devices. Broader Application: Platform adaptable for other acute pulmonary diseases with similar pathophysiology.

Acute Respiratory Distress Syndrome, ARDS, SDRA, Lung injury, Pulmonary inflammation, Mesenchymal stem cells, MSCs, Extracellular vesicles, EVs, MicroRNAs, miRNAs, Immunomodulation, Tissue regeneration, Nanomedicine, PLGA nanocapsules, Biodegradable polymers, Controlled release, Inhalation therapy, Nebulization, Aerogen Ltd., Translational medicine, ICU, Ventilatory support, Hypoxemia, Molecular therapy, Advanced therapies, Patent PCT/EP2025/054944, Drug delivery, Local administration, Systemic side effects, Clinical feasibility, Preclinical validation, Biomedical innovation, Respiratory failure, Inflammatory pathways, Alveolar repair, Biotechnological platform, FDA-approved materials, Health economics, Cost reduction, Hospitalization costs, Rehabilitation, Socioeconomic impact, Mortality reduction, Nanotechnology, Pulmonary diseases, Translational research, Pharmaceutical industry, Biotechnology, Public health impact.