Intranasal administration of a multiplex targeting SCLMs@FEN1-hpDNAs with synergistic baicalein for pulmonary anti-viral treatment

Here we reported an anti-viral strategy for SARS-CoV-2 infection: intranasal administration of silica cross-linked micelles (SCLMs) encapsulating in vitro purified NES-FEN1-NES protein and a set of hpDNAs (shorted as SCLMs@FEN1-hpDNAs). The set of hpDNAs multiplex targeted SARS-CoV-2's N gene RNA and the host Ctsl gene mRNA. In vitro experiments demonstrated the purified NES-FEN1-NES protein transfected into cells has efficient mRNA knockdown ability when guided by hpDNAs. The intranasal administration of SCLMs exhibited high pulmonary accessibility, and SCLMs@FEN1-hpDNAs effectively downregulated targeted gene expression in vivo. The efficacy is enhanced by synergistic intranasal baicalein by improving cellular uptake and anti-inflammatory effects. In a mouse model of SARS-CoV-2 infection, the combination with baicalein and SCLMs@FEN1-hpDNAs inhibited the virus replication, improved survival rates, and reduced neuroinflammation. This study highlights the potential of intranasal SCLMs@FEN1-hpDNAs with baicalein as a promising approach for treating respiratory diseases. Overall design: To examine the intensity of the collateral effects of the FEN1-hpDNA, we performed total RNA integrity analysis and transcriptome-wide RNA-seq of A549 cells treated with FEN1-hpDNA. Data showed that ~ 44 and 107 genes were significantly up-regulated and down-regulated in FEN1-hpDNA group compared with the NT control, respectively .