Seungju Yang

Interferon‐λ (IFN‐λ), a type III interferon that selectively targets epithelial cells, holds strong potential as an intranasal antiviral due to its ability to suppress respiratory virus replication without inducing systemic inflammation. However, clinical translation of human IFN‐λ3 (hIFN‐λ3) is hindered by limited thermostability, protease susceptibility, and rapid mucosal clearance. In this study, instability‐prone elements in hIFN‐λ3 are eliminated through artificial intelligence (AI)‐based backbone remodeling and targeted surface hydrophobic patch engineering. A protease‐sensitive loop is replaced with a de novo α‐helix, which shields neighboring hydrophobic patches and forms a new hydrophobic core, yielding an engineered variant (hIFN‐λ3‐DE1) with enhanced thermostability (Tm > 90 °C), protease resistance, and preserved antiviral activity and structural integrity even after extended heat stress (two weeks at 50 °C). Further glyco‐engineering introduces an N‐linked glycan at a site distant from receptor‐binding interfaces, improving solubility, production yield, and diffusion through synthetic nasal mucus. Intranasal administration of the resulting variant (G‐hIFN‐λ3‐DE1) enables effective mucosal penetration and provides a more rapid onset of in vivo prophylactic protection against influenza A virus. These findings highlight a robust and versatile strategy that combines AI‐driven structural design with glyco‐engineering to develop scalable, bioavailable, and functionally enhanced nasal biologics for respiratory virus prophylaxis.

Drug‐resistant microorganisms cause serious problems in human healthcare, leading to the persistence in infections and poor treatment outcomes from conventional therapy. In this study, a gene‐targeting strategy using microbubble‐controlled nanoparticles is introduced that can effectively eliminate biofilms of methicillin‐resistant Staphylococcus aureus (MRSA) in vivo. Biofilm‐targeting nanoparticles (BTN) capable of delivering oligonucleotides are developed that effectively remove biofilm‐associated bacteria upon controlled delivery with diatom‐based microbubblers (MB). The activity of BTN in silencing key bacterial genes related to MRSA biofilm formation ( icaA ), bacterial growth ( ftsZ ), and antimicrobial resistance ( mecA ), as well as their multi‐targeting ability in vitro is validated. The integration of BTN with MB is next examined, resulting in synergistic effects in biofilm removal and antimicrobial activity in an ex vivo porcine skin model. The therapeutic efficacy is further investigated in vivo in a mouse wound model infected with MRSA biofilm, which showed that MB‐controlled BTN delivery substantially reduced bacterial load and led to the effective elimination of the biofilm. This study underscores the potential of the gene silencing platform with physical enhancement as a promising strategy to combat problems related to biofilms and antibiotic resistance.

Interferon-λ (IFN-λ), a type III interferon that selectively targets epithelial cells, holds strong potential as an intranasal antiviral due to its ability to suppress respiratory virus replication without inducing systemic inflammation. However, clinical translation of human IFN-λ3 (hIFN-λ3) is hindered by limited thermostability, protease susceptibility, and rapid mucosal clearance. In this study, instability-prone elements in hIFN-λ3 are eliminated through artificial intelligence (AI)-based backbone remodeling and targeted surface hydrophobic patch engineering. A protease-sensitive loop is replaced with a de novo α-helix, which shields neighboring hydrophobic patches and forms a new hydrophobic core, yielding an engineered variant (hIFN-λ3-DE1) with enhanced thermostability (Tm >90 °C), protease resistance, and preserved antiviral activity and structural integrity even after extended heat stress (two weeks at 50°C). Further glyco-engineering introduces an N-linked glycan at a site distant from receptor-binding interfaces, improving solubility, production yield, and diffusion through synthetic nasal mucus. Intranasal administration of the resulting variant (G-hIFN-λ3-DE1) enables effective mucosal penetration and provides robust prophylactic protection against influenza A virus infection in an in vivo mouse model. These findings highlight a robust and versatile strategy that combines AI-driven structural design with glyco-engineering to develop scalable, bioavailable, and functionally enhanced nasal biologics for respiratory virus prophylaxis.

Respiratory virus infections continue to pose a substantial global health challenge, requiring effective prophylactic and therapeutic strategies. Type III interferon (IFN-λ) has shown promise as an antiviral agent that strongly inhibits viral replication while minimizing systemic inflammation. Intranasal administration of IFN-λ allows easy access to the respiratory mucosa, enhancing localized antiviral responses. However, clinical application of IFN-λ is hindered by rapid mucociliary clearance, limited mucosal adhesion, and susceptibility to proteolytic degradation. Here, we develop nanoliposomes that can deliver IFN-λ through an intranasal route (NLp@IFN-λ) and act as an effective antiviral. We demonstrate that the nanoliposomes enable efficient penetration of IFN-λ in a mucus-mimicking model while allowing controlled release of the protein in vitro. NLp@IFN-λ treatment could effectively up-regulate interferon-stimulated genes in A549 cells, without inducing cytotoxicity. Finally, in vivo delivery of NLp@IFN-λ through a nasal route demonstrates prolonged retention and reduces viral load in nasal tissues in an infection model with influenza virus. This study demonstrates the potential of NLp@IFN-λ as an effective nasal delivery platform for prophylaxis of respiratory virus infections.