Oral nanoformulation of a host-directed antiviral niclosamide effectively treats severe fever with thrombocytopenia syndrome

Severe fever with thrombocytopenia syndrome (SFTS), caused by the tick-borne Dabie bandavirus (DBV), is a serious public health concern due to its high morbidity and mortality rates. However, no antiviral treatment has been developed for SFTS. Through target-focused screening, we identified five anti-SFTS candidates: niclosamide (NIC), cepharanthine, nifedipine, zanamivir, and ivacaftor. Among the 5, NIC showed the highest potency (IC₅₀ = 0.37 μM, CC₅₀ > 50 μM; SI > 135.14). Despite NIC's strong antiviral activity against DBV, its poor bioavailability limited therapeutic application. To address this, we developed NCNP-NIC, an oral nanoparticle formulation encapsulating NIC with tauroursodeoxycholic acid (TUDCA) via non-covalent interactions. NCNP-NIC formed spherical particles (NIC: TUDCA = 1:4) with an average size of 181 ± 5.02 nm and a polydispersity index of 0.176 ± 0.09. The nanoformulation improved NIC's bioavailability to 52.7 %, a 13-fold increase over pure NIC (4.01 %). As NCNP-NIC involved only non-covalent assembly without new chemical entities, no toxicity was observed. Oral administration of NCNP-NIC at both low (20 mg/kg) and high (40 mg/kg) doses completely cured SFTS in IFNAR-/- mouse model. This work establishes NCNP-NIC as a promising oral therapy for SFTS, while its innovative nanoformulation provides a versatile platform for improving the bioavailability of other poorly soluble antiviral drugs.