A viral infection-biomimetic strategy for antibody-guided targeted protein degradation.

Targeted protein degradation (TPD) is a valuable strategy for investigating protein functionality in cell biology and drug discovery. Among the various emerging TPD technologies, antibody-guided TPD offers key advantages over other protein degradation methods in terms of compatibility with different proteins of interest (POIs) and cell types. However, increasing the efficiency of cellular antibody internalisation and protein degradation remains challenges. Inspired by viral infection, which often efficiently activates protein degradation pathways in host cells, we developed a strategy called virus infection-mimicking targeted protein degradation (ViTPD) as a universal platform for degrading intracellular proteins. By mimicking three features of viral infection, we produced ViTPD nanoparticles by biomineralising antibodies enveloped by viral membranes or mixed with IFN-α. The biomineralised shell enhanced the cellular uptake of ViTPD nanoparticles via clathrin-mediated endocytosis. Similar to viral neutralising antibodies entering cells, the Fab region of the antibody released from ViTPD nanoparticles binds the POI, while the Fc region can recruit TRIM21, a key enzyme that continuously consumes during protein degradation. Interestingly, viral membrane components or IFN-α in the ViTPD led to increased TRIM21 expression, which enhanced the efficiency of proteolysis. ViTPD can effectively degrade several POIs, including GFP, FAK, COPZ1 and TREX1. Collectively, our results demonstrate that ViTPD provides a novel design strategy and an efficient nanoplatform for targeting intracellular protein degradation. STATEMENT OF SIGNIFICANCE: Antibody-guided targeted protein degradation (TPD) exhibits superior versatility compared to conventional degradation methods, demonstrating broad compatibility with diverse proteins of interest (POIs) across various cell types. Despite these advantages, significant challenges persist in optimizing cellular antibody internalization efficiency and degradation kinetics. In this study, we developed ViTPD, a biomimetic TPD platform that mimicking three viral infection features: (1) virus-like cellular internalization pathways, (2) virus-neutralizing antibody behavior, and (3) host-mediated protein degradation responses during viral infection. The development of ViTPD provides not only a robust platform for degrading diverse intracellular POIs but also establishes new design principles for next-generation protein degradation systems. This platform establishes new design principles for next-generation TPD systems while expanding therapeutic potential for precision medicine.