• TRIM21 (ΔBB), a B-box domain deletion variant, significantly enhances targeted protein degradation efficiency compared to wild-type TRIM21 and other engineered constructs.
• The TRIM21 (ΔBB) system effectively degrades HPV oncoproteins E6 and E7 in both exogenous and endogenous (CaSki) settings, offering a potential therapeutic strategy for HPV-associated cancers.
• The study demonstrates that domain engineering of E3 ligases can optimize antibody-based TPD technologies, providing a versatile platform for targeted protein degradation.
• The Fc-nanobody approach enables specific targeting of proteins for degradation, with potential applications in research and clinical interventions.