Mast Cell‐Targeted Gas Therapeutic Strategy: Intelligent H 2 S‐Donor Nano‐Stabilizer for the Long‐Term Treatment of Allergic Diseases In Vivo

ABSTRACT Allergic diseases driven by dysregulated mast cell activation remain a major clinical challenge due to the repeated long‐term dosing and severe side effects of current small‐molecule stabilizers. Gas therapy offers a promising alternative owing to its high biocompatibility, minimal toxicity, and stimulus‐responsive release. Hydrogen sulfide (H 2 S), an endogenous gas mediator involved in inflammatory regulation, has not yet been explored for the treatment of allergic inflammation. Herein, a mast cell‐targeted H 2 S gas therapeutic strategy was developed for the long‐term treatment of allergic diseases. Biodegradable mesoporous organosilica nanoparticles incorporating tetrasulfide bridges were rationally designed, loaded with sodium cromoglicate, and surface‐modified with hyaluronic acid (HA) to construct the nano‐stabilizer ( S MSNs@SC@HA ). HA coating enabled mast cell targeting and prevented premature drug leakage. Intracellular glutathione triggered sustained (>24 h) H 2 S release via tetrasulfide bond cleavage, suppressing mast cell degranulation through antioxidative effects and AMP‐activated kinase (AMPK) activation, while simultaneously inducing carrier degradation and controlled drug release. This system represents the first H 2 S‐donating nanoplatform for targeted mast cell delivery, achieving synergistic anti‐allergic efficacy. In vivo studies in passive cutaneous anaphylaxis and allergic asthma models demonstrated high therapeutic efficacy, prolonged treatment duration, and negligible inflammatory side effects, highlighting its strong potential for clinical translation.