Intratracheal Extracellular Matrix‐Mimetic Hydrogel Modulates Immune Homeostasis for Asthma Therapy

ABSTRACT Glucocorticoids, while central to asthma management, face clinical challenges due to systemic toxicity and acquired resistance, underscoring an urgent demand for novel targeted therapies. Here, a bioinspired hydrogel derived from decellularized lung extracellular matrix (dECM) is engineered for the localized and synchronized co‐delivery of methylprednisolone (MP) and resveratrol (RSV). The resulting RML@dECM platform demonstrates excellent biocompatibility and provides sustained release of both agents within the bronchial microenvironment. Therapeutically, the system effectively alleviates asthma pathology via dual immunomodulatory and anti‐remodeling actions. Mechanistically, RML@dECM restores pulmonary immune homeostasis by rebalancing Th1/Th2 responses and repolarizing macrophages from a pro‐fibrotic M2 toward a protective M1 phenotype, while concurrently inhibiting mucus hypersecretion through modulation of the JAK/STAT signaling pathway. In vivo, RML@dECM surpasses conventional corticosteroid monotherapy, markedly reducing airway hyperresponsiveness, mucus overproduction, and histological damage. Importantly, by confining drug action to the lungs, the platform significantly minimizes systemic exposure and off‐target adverse effects. This work presents a synergistic, locally delivered dual‐drug hydrogel that addresses core limitations in asthma treatment, offering a promising translational strategy for achieving sustained airway immunomodulation with enhanced safety.