pH-Smart Nanocarrier Delivers miR-146a to Slash Allergic Rhinitis Inflammation

Allergic rhinitis (AR) affects up to 50% of populations in some countries and often resists standard pharmacotherapy and immunotherapy. Its complex pathophysiology—dominated by Th2-skewed adaptive immunity and innate immune dysregulation—demands new therapeutic targets and delivery strategies. MicroRNA-146a (miR-146a) is a well-established negative regulator of NF-κB signaling and Th2 polarization, but its therapeutic use has been hampered by rapid nuclease degradation and poor mucosal bioavailability when administered as free nucleic acid.

The research team fabricated amine-modified mesoporous silica nanoparticles (NH2-MSNs) with large specific surface areas capable of electrostatically loading negatively charged miR-146a mimics. These miRNA-loaded particles were then embedded within a chitosan hydrogel crosslinked with sodium tripolyphosphate, creating the Gel/MSN-miR146a composite. Because chitosan becomes increasingly soluble under acidic conditions—matching the pH 5.5–6.5 nasal mucosa of AR patients—the platform provides pH-triggered, sustained release of miR-146a precisely at the inflamed site. In vitro release studies confirmed significantly accelerated miRNA release at pH 6.0 versus pH 7.4 or 8.0.

In an OVA-sensitized Sprague-Dawley rat AR model, intranasal Gel/MSN-miR146a administered daily for 7 days achieved superior mucosal retention compared with free miR-146a (IVIS imaging at 6, 24, and 48 hours), and produced marked reductions in nasal rubbing frequency, serum IgE, and Th2 cytokines (IL-4, IL-5, IL-13). Mechanistically, the nanocarrier boosted local miR-146a levels, leading to effective downregulation of its canonical targets IRAK1 and TRAF6, and consequent suppression of NF-κB activation. Crucially, the study demonstrated for the first time in AR that miR-146a also potently suppresses the NLRP3 inflammasome/caspase-1/GSDMD pyroptosis axis, reducing IL-1β and IL-18 release. This pyroptosis–Th2 crosstalk amplification loop was validated by nigericin rescue experiments: intranasal co-administration of the NLRP3 activator nigericin reversed the anti-AR benefits of Gel/MSN-miR146a, confirming that pyroptosis suppression is mechanistically necessary, not merely correlative.

Biocompatibility was systematically characterized through 15-day subacute toxicity studies in rodents and in vitro cellular assays in human nasal epithelial cells (HNEpCs) and primary CD4+ T cells, with no significant adverse findings. Taken together, the Gel/MSN platform represents a clinically translatable nanomedicine approach: non-invasive intranasal administration, acid-triggered local release, and a dual anti-inflammatory mechanism targeting both adaptive and innate immune pathways in AR.