Abstract
Macrophages' activation plays a central role during the development and progression of inflammation, while the regulation of metabolic reprogramming of macrophages has been recently identified as a novel strategy for anti‐inflammatory therapies. Our previous studies have found that tetrahedral framework nucleic acid (tFNA) plays a mild anti‐inflammatory effect by inhibiting macrophage activation, but the specific mechanism remains unclear. Here, by metabolomics and RNA sequencing, choline uptake is identified to be significantly repressed by decreased
slc44a1
expression in tFNA‐treated activated macrophages. Inspired by this result, combined with the excellent delivery capacities of tFNA, siR‐slc44a1 is loaded into the tFNA to develop a new tFNA‐based small interfering RNA (siRNA) delivery system named ‘nano‐windmill,’ which exhibits a synergetic role by targeting
slc44a1
, finally blowing up the anti‐inflammatory effects of tFNA to inhibit macrophages activation via reducing choline uptake. By confirming its anti‐inflammatory effects in chronic (periodontitis) and acute (sepsis) inflammatory disease, the tFNA‐based nanomedicine developed for inflammatory diseases may provide broad prospects for tFNA upgrading and various biological applications such as anti‐inflammatory.
A tFNA‐based nanomedicine named ‘nano‐windmill,’ which loads siR‐slc44a1 on tFNA through a sticky end containing RNase H‐responsive sequence, is developed to amplify the anti‐inflammatory effects of tFNA by synergistically decreasing
slc44a1
expression, thus reducing choline uptake, and finally inhibiting macrophages overactivation. This novel tFNA‐based siRNA delivery system paves the way for the development of new nanomedicine with superior anti‐inflammatory effects.