Multi‐Route Administration Delivery System Based on Tetrahedral Framework Nucleic Acids for Alleviating Type I Hypersensitivity Reactions

Abstract Type I hypersensitivity reactions are the most common type of hypersensitivity reactions and can cause various symptoms in different body systems. Currently, there is no standard treatment for the different manifestations of type I hypersensitivity reactions at different sites. To address this challenge, a nanocomposite named tFNAs‐siRNA‐siRNA (TSS) is designed based on tetrahedral framework nucleic acids (tFNAs). It is loaded with two siRNAs and can enter the body through multi‐route administration. In terms of the realization of siRNAs’ functions, TSS successfully delivers them and downregulates the expression of Gab2 and Syk, thereby inhibiting the migration and release of granules to the extracellular space in RBL‐2H3 cells. Interestingly, TSS also exhibits the effect of hindering Ca²⁺ efflux from mitochondria to stabilize energy metabolism. In the passive cutaneous anaphylaxis and allergic rhinitis model, TSS shows excellent anti‐allergic ability, and demonstrates an advantage in intraperitoneal injection, transdermal, and transnasal routes of administration. In sum, TSS offers a new therapeutic strategy for type I hypersensitivity reactions with multiple symptoms, highlighting the application potential of nucleic acids‐based multi‐route administration delivery system.