BBTS25 nanocomplex, combining baicalin and TS25 peptide, delivers broad-spectrum antiviral activity in fish.

The persistent global threat of viral diseases necessitates innovative antiviral strategies that overcome the limitations of conventional therapeutics, such as narrow antiviral spectrum, rapid resistance development, and insufficient immune engagement. Current treatments often fall short in providing broad-spectrum protection or robust host immune activation. This study addresses this gap by developing a novel "drug-delivering-drug" nanocomplex, leveraging the synergistic potential of natural compounds and bioactive peptides to reinforce host innate immunity, specifically through the type I interferon pathway, for a more durable and comprehensive antiviral response.

Researchers developed BBTS25, a carrier-free, "drug-delivering-drug" antiviral nanocomplex, through the directed self-assembly of baicalin and the bioactive peptide TS25. In vitro, they evaluated BBTS25's ability to suppress viral replication, reduce intracellular and supernatant viral loads, and compromise virion structural integrity. Atomistic molecular dynamics simulations were used to investigate cellular membrane penetration and peptide-nucleic acid interactions. Transcriptomic profiling of treated cells assessed gene network induction. In vivo, BBTS25 was administered to a teleost (fish) model to evaluate survival and biocompatibility, followed by spleen transcriptomic analysis and quantitative PCR to assess immune responses.

BBTS25 exhibited potent broad-spectrum antiviral efficacy. In a representative viral model, it strongly suppressed viral replication, reducing intracellular viral loads by approximately 70% and supernatant viral loads by approximately 80%, while concurrently compromising virion structural integrity. Mechanistically, atomistic molecular dynamics simulations revealed that BBTS25 efficiently penetrates cellular membranes, with its peptide component forming strong interactions with intracellular nucleic acids. This interaction shields nucleic acids from nuclease-mediated degradation, thereby sustaining the activation of the type I interferon pathway. Consistently, transcriptomic profiling of treated cells showed robust induction of interferon-stimulated gene networks and activation of innate antiviral responses. In vivo, BBTS25 administration in a lower vertebrate (teleost) model enhanced survival by approximately 47% and demonstrated excellent biocompatibility. Furthermore, spleen transcriptomic analysis and quantitative PCR indicated that BBTS25 activates dendritic cells and macrophages, and promotes type I interferon-associated immune responses.

BBTS25 significantly reduced intracellular viral loads by approximately 70% and supernatant viral loads by approximately 80% in a representative viral model.