(T1530-08-48) Significant Antiasthmatic Effect of Receptor-Guided Parenteral RNAi-Loaded Polymeric Nanocarriers in Murine Asthma Model

Purpose: To develop and evaluate receptor-targeted gelatin nanocarriers (GNCs) loaded with STAT6 siRNA (S6S) and conjugated with an IL-4R-targeting peptide (S6S-GNC-P), aiming to enhance targeted delivery and suppress asthma-associated inflammation.

Methods: Formulation: S6S-GNC-P was synthesized using a two-step desolvation method, followed by PEGylation and conjugation with an IL-4R-binding peptide. The developed formulation was tested in vitro in asthma-associated cell-based assays. In Vivo Study: Mice were divided into four treatment groups: a negative control (asthmatic + saline, Group H), a healthy control (Group G), and a treatment group (asthmatic + S6S-GNC-P, Group D).

Assessment: Airway hyperresponsiveness was evaluated using methacholine challenge to measure specific airway resistance (Figure A).

Results: The IL-4 receptor guided STAT6 siRNA-loaded. Gelatin-based nanocarriers with diameters ranging from 100 to 300 nm and cationic charge were developed. The developed nanocarriers exhibited significant enhancement in the anti-inflammatory effect against Th2 cells. The house dust mite allergen-based murine model of asthma was validated by a substantial increase in airway resistance in Group H (asthmatic + saline) compared to Group G (healthy control) (p < 0.05). Treatment with S6S-GNC-P (Group D) restored airway resistance to levels comparable to healthy controls (Group G) (p > 0.05), indicating effective suppression of asthma symptoms. All other treatment groups showed statistically significant improvement compared to the saline-treated asthmatic group (Figure B).

Conclusion: The IL-4R-targeted, PEGylated gelatin nanocarrier system (S6S-GNC-P) facilitated the efficient delivery of STAT6 siRNA, leading to the effective silencing of asthma mediators and the reversal of disease symptoms in a murine model. This formulation presents a promising receptor-guided therapeutic strategy for asthma.

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Figure. A. Chronic asthma house dust mite allergen murine model and B. Antiasthmatic effect of in murine model.