Mechanochemically-reprogrammed stem cell exosomes reconcile the biogenesis-internalization trade-off for pulmonary fibrosis therapy

Abstract Matrix stiffness serves as a pivotal biophysical cue that profoundly dictates exosome biogenesis and cellular internalization, yet often creates a functional trade-off that impedes clinical translation. Herein, we developed a mechano-chemo-transductive strategy to engineer mesenchymal stem cell (MSC) exosomes endowed with robust biogenesis and superior delivery potency. Specifically, we revealed that MSCs cultured on soft matrices secreted a significantly elevated exosome yield and demonstrated enhanced competence to drive macrophage towards anti-inflammatory M2 polarization. Conversely, stiff matrices upregulated ATP-binding cassette transporter A1 (ABCA1) expression, enriching exosomal membrane cholesterol and facilitating cellular internalization by recipient cells. By taking advantages of these unique mechano-responses, we engineered MSCs via substrate softening combined with ABCA1 modulation to generate mechanochemically reprogrammed exosomes with concurrently enhanced yield and internalization efficiency. In a murine model of pulmonary fibrosis characterized by restrictive biological barriers, inhaled mechanochemically reprogrammed exosomes treatment demonstrated superior lung retention and deep tissue penetration. Furthermore, they effectively orchestrated immune homeostasis by repolarizing alveolar macrophages to reverse fibrotic remodeling and restore lung function. Collectively, by reconciling the intrinsic trade-off between biogenesis and cellular uptake, this strategy represents a paradigm shift in exosome engineering and paves the way for next-generation therapeutics against refractory fibrotic diseases.