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Here, we present a programmable, nanobody\u2010based targeted protein degradation platform, termed Nanobody\u2010Targeting Chimera (Nab\u2010TAC), designed for the intracellular clearance of HBV antigens. To systematically identify functional degradation modules, we developed a split\u2010luciferase complementation\u2010based quantitative screening platform that benchmarks degron motifs and proximity\u2010inducing effectors, enabling comprehensive ranking of proteasome\u2010 and lysosome\u2010targeting elements across diverse cellular contexts and subcellular compartments. By coupling phage display\u2010derived nanobodies and single\u2010chain variable fragments with these optimized degradation modules, we engineered a panel of Nab\u2010TAC constructs that efficiently degrade viral HBsAg in hepatocytes. Notably, the lead construct, E3\u2010FCGR3B, achieved robust intrahepatic antigen clearance and markedly reduced circulating HBsAg levels in an HBV hydrodynamic injection mouse model. Together, these findings establish Nab\u2010TAC 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.<\/jats:p>","DOI":"10.1002\/advs.76687","type":"journal-article","created":{"date-parts":[[2026,7,17]],"date-time":"2026-07-17T20:21:08Z","timestamp":1784319668000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Programmable Nanobody\u2010Targeting Chimeras Enable Intracellular Viral Protein Degradation"],"prefix":"10.1002","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8927-9081","authenticated-orcid":false,"given":"Max Yu\u2010Chen","family":"Pan","sequence":"first","affiliation":[{"name":"Institute of Molecular and Cellular Biology National Tsing Hua University  Hsinchu Taiwan"},{"name":"SMOBIO Technology, Inc.  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