Targeted degradation of Influenza a virus nucleoprotein via aptamer-based PROTACs for antiviral therapy

Influenza A virus (IAV) poses a serious threat to public health due to its high mutability and rapid transmissibility. The viral nucleoprotein (NP), a highly conserved and essential component, has emerged as an ideal target for antiviral therapies. However, its biological function has proven challenging to modulate with conventional drugs, and no NP-targeting therapeutics have reached the market so far. Here, we report the development and application of an aptamer-based proteolysis-targeting chimera (PROTAC) for the targeted degradation of IAV NP. Utilizing the Direct-to-Biology (D2B) platform, we efficiently screened and identified NP-PROTAC#4 as a functional candidate. Subsequently, we developed a lipid nanoparticle (LNP) formulation of NP‑PROTAC#4 (LNP@NP‑PROTAC#4) for effective intracellular delivery. Importantly, LNP@NP-PROTAC#4 demonstrated potent antiviral activity both in vitro and in vivo. Mechanistically, NP-PROTAC#4 exerts its antiviral effects by targeting and degrading NP via the ubiquitin-proteasome system. In conclusion, our findings provide the first evidence that NP-targeted PROTAC degrader exhibits therapeutic effects, proposing a novel therapeutic strategy for IAV.