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Inhibition of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and excessive inflammation is the current task in the prevention and treatment of COVID-19. Here, we designed a dual-function circular aptamerASO chimera (circSApt-NASO) to suppress SARS-CoV-2 replication and inflammation. The chemically unmodified circSApt-NASO exhibited high serum stability by artificial cyclization, significantly enhancing the utility of oligonucleotides. It presents great efficiency in knocking down, demonstrating the superiority of the circular ASO as a novel tool for sequence-specific silencing of gene expression. Furthermore, we propose and demonstrate that the SApt binding to spike protein enables the chimera to be efficiently delivered into the susceptible host cells expressing ACE2 along with the infection of SARS-CoV-2. At high concentrations of SARS-CoV-2, the efficiency of targeted delivery of circSApt-NASO can even be compared to transfection. Among them, the anti-spike aptamer (SApt) that blocks the Spike-TLR4 interaction potently inhibits spike-induced inflammation. The NASO targeting to silence N genes not only display robust anti-N-induced inflammatory activity, but also achieve efficient inhibition of SARS-CoV-2 replication. Therefore, benefiting from the high stability of the cyclization, anti-spike aptamer-dependent and viral infection-mediate targeted delivery, the circSApt-NASO displays robust potential against authentic SARS-CoV-2 and Omicron (B.1.1.529), providing a promising specific anti-inflammatory and anti-proliferative reagent for therapeutic COVID-19 based on the oligonucleotide therapeutics strategy.

Infections caused by drug-resistant "superbugs" pose an urgent public health threat due to the lack of effective drugs; however, certain mammalian proteins with intrinsic antibacterial activity might be underappreciated. Here, we reveal an antibacterial property against Gram-negative bacteria for factors VII, IX and X, three proteins with well-established roles in initiation of the coagulation cascade. These factors exert antibacterial function via their light chains (LCs). Unlike many antibacterial agents that target cell metabolism or the cytoplasmic membrane, the LCs act by hydrolyzing the major components of bacterial outer membrane, lipopolysaccharides, which are crucial for the survival of Gram-negative bacteria. The LC of factor VII exhibits in vitro efficacy towards all Gram-negative bacteria tested, including extensively drug-resistant (XDR) pathogens, at nanomolar concentrations. It is also highly effective in combating XDR Pseudomonas aeruginosa and Acinetobacter baumannii infections in vivo. Through decoding a unique mechanism whereby factors VII, IX and X behave as antimicrobial proteins, this study advances our understanding of the coagulation system in host defense, and suggests that these factors may participate in the pathogenesis of coagulation disorder-related diseases such as sepsis via their dual functions in blood coagulation and resistance to infection. Furthermore, this study may offer new strategies for combating Gram-negative "superbugs".