A pH-responsive miR-146a-loaded Gel/MSN nanocarrier enhances anti-inflammatory efficacy in allergic rhinitis through pyroptosis suppression

BACKGROUND: Allergic rhinitis (AR) is characterized by Th2-dominant inflammation. MicroRNA-146a (miR-146a) is a critical regulator of immune balance in AR, yet its therapeutic translation is severely limited by poor stability and inefficient local delivery. This study aimed to construct a pH-responsive chitosan-coated mesoporous silica (Gel/MSN) nanocarrier for the efficient intranasal delivery of miR-146a, and to evaluate its therapeutic efficacy and underlying mechanisms in AR. METHODS: The Gel/MSN platform was fabricated and characterized for its structural properties, miR-146a loading efficiency, and pH-triggered release profile. For in vivo evaluation, the nanocomposite was administered intranasally to an AR rat model. Therapeutic efficacy was assessed via behavioral scoring, serum IgE measurements, and the analysis of Th2 cytokines and pyroptosis-related mediators in the nasal mucosa. Biocompatibility was systematically evaluated through 15-day subacute toxicity studies and in vitro cellular assays. RESULTS: The synthesized Gel/MSNs possessed a well-defined mesoporous structure with a high specific surface area, enabling efficient miR-146a loading and sustained release under weakly acidic conditions. In vivo, Gel/MSN-miR146a exhibited excellent biocompatibility and markedly alleviated acute nasal symptoms in AR rats, significantly outperforming free miR-146a in reducing serum IgE and Th2 cytokine levels. Mechanistically, the nanocarrier enhanced local miR-146a bioavailability, effectively downregulating the IRAK1/TRAF6/NF-κB axis. Crucially, this treatment strongly suppressed the expression of pyroptosis-related proteins (NLRP3, Caspase-1, GSDMD) and effector cytokines (IL-1β, IL-18). Rescue experiments with the pyroptosis activator nigericin reversed the ameliorative effects of Gel/MSN-miR146a, confirming that pyroptosis suppression is essential for its anti-AR efficacy. CONCLUSIONS: We successfully developed a biocompatible, pH-responsive Gel/MSN nanocarrier for the efficient intranasal delivery of miR-146a. This platform exerts potent anti-AR effects via a dual mechanism: inhibiting Th2-driven inflammation and suppressing pyroptosis, offering a highly promising and translatable nanotherapeutic strategy for clinical AR management.