Lily Hui-Ching Wang

Chronic hepatitis B virus (HBV) infection remains a major global health challenge, largely because current antiviral therapies seldom achieve sustained clearance of the viral surface antigen (HBsAg), a central driver of immune tolerance and viral persistence. Here, we present a programmable, nanobody-based targeted protein degradation platform, termed Nanobody-Targeting Chimera (Nab-TAC), designed for the intracellular clearance of HBV antigens. To systematically identify functional degradation modules, we developed a split-luciferase complementation-based quantitative screening platform that benchmarks degron motifs and proximity-inducing effectors, enabling comprehensive ranking of proteasome- and lysosome-targeting elements across diverse cellular contexts and subcellular compartments. By coupling phage display-derived nanobodies and single-chain variable fragments with these optimized degradation modules, we engineered a panel of Nab-TAC constructs that efficiently degrade viral HBsAg in hepatocytes. Notably, the lead construct, E3-FCGR3B, achieved robust intrahepatic antigen clearance and markedly reduced circulating HBsAg levels in an HBV hydrodynamic injection mouse model. Together, these findings establish Nab-TAC as a modular and versatile platform for targeted antiviral protein degradation and highlight its potential as a therapeutic strategy toward a functional cure for chronic HBV infection.

The long-term effectiveness of paclitaxel is limited by chemoresistance. In this study, we elucidate the molecular mechanism by which kinesin family member 2C (KIF2C), a well-known microtubule depolymerase, contributes to the development of chemoresistance in triple-negative breast cancer (TNBC). We observed elevated levels of KIF2C, tubulin tyrosination, and polyglutamylation in human and mouse breast cancer cells resistant to paclitaxel. Additionally, these chemoresistant cells possessed cross-resistance to diverse microtubule-targeting agents (MTAs). We demonstrated that KIF2C preferentially depolymerizes polyglutamylated tubulin, even in the presence of paclitaxel. To counter this, we developed 7S9, a chemical inhibitor of KIF2C, that prohibits the dissociation of KIF2C from microtubules. The combination of 7S9 and paclitaxel significantly reduced tumorigenesis in chemoresistant TNBC model in mice. Moreover, 7S9 diminished cancer cell chemoresistance to several clinically available MTAs. Our findings elucidate the molecular mechanism of KIF2C-mediated chemoresistance and highlight KIF2C as a promising target for combating cross-resistance in TNBC.