Desarrollo de una nueva terapia para el SDRA basada en la identificación de miRNAs de vesículas extracelulares derivadas de células madre

• Dra. Aina Areny Balagueró

Dr. Antonio Artigas Raventós and Dr. Daniel Closa Autet

Fisiopatología respiratoria en el paciente crítico del grupo A8G3 – Investigación traslacional en el paciente crítico, en el Instituto de Investigación e Innovación Parc Taulí (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.

La tesis propone una estrategia terapéutica innovadora para el síndrome de dificultad respiratoria aguda (SDRA), una afección con alta mortalidad y sin tratamientos específicos efectivos. El enfoque se basa en: Concepto terapéutico: Nanocápsulas inhalables de PLGA (polímero biodegradable) cargadas con una combinación patentada de microARN (miARN) con propiedades inmunomoduladoras y regenerativas. Fundamento científico: Los miARN se identificaron a partir de vesículas extracelulares secretadas por células madre mesenquimales (MSC) en condiciones inflamatorias, dirigiéndose a vías clave para la resolución de la inflamación y la reparación alveolar. Sistema de administración: La encapsulación en nanocápsulas de PLGA mejora la estabilidad, controla la liberación y permite la administración pulmonar directa por inhalación, minimizando los efectos sistémicos. Traducción clínica: La colaboración con Aerogen Ltd. demostró una nebulización eficiente utilizando dispositivos clínicamente aprobados, lo que respalda la viabilidad de la integración en las rutinas de soporte ventilatorio de la UCI. Impacto: Clínico: Potencial para reducir la estancia en la UCI, acelerar la recuperación y disminuir la mortalidad y las secuelas a largo plazo. Económico: Ahorro significativo de costos al reducir las necesidades de hospitalización y rehabilitación. Comercial: Alto potencial de valorización gracias a la combinación patentada de miRNA, un sistema de administración aprobado por las autoridades regulatorias y la compatibilidad con dispositivos médicos existentes. Aplicación más amplia: Plataforma adaptable a otras enfermedades pulmonares agudas con fisiopatología similar.

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.