Nanogel-Facilitated Protein Intracellular Specific Degradation through Trim-Away

The recently discovered “Trim-Away” mechanism opens a new window for fast and selective degradation of endogenous proteins. However, the in vivo and clinical application of this approach is hindered by the requirement of special skills and equipment needed for the intracellular delivery of antibodies. Here, an antibody conjugated polymer nanogel system, nanogel-facilitated protein intracellular specific degradation (Nano-ERASER), for intracellular delivery and release of antibody, and degradation of a specific endogenous protein is developed. After being delivered into cells, the antibody is released and forms a complex with its target protein, and subsequently binds to the Fc receptor of Tripartite motif 21 (TRIM21). The resulting complex of target protein/antibody/TRIM21 is then degraded by the proteasome. The efficacy of Nano-ERASER is validated by depleting GFP protein in a GFP expressing cell line. Furthermore, Nano-ERASER successfully degrades the coatomer protein complex ζ1, a vital protein for cancer cells, and kills those cells while sparing normal cells. Benefitting from its convenience and targeted delivery merit, Nano-ERASER technique is promising in providing a reliable tool for endogenous protein function study as well as paves the way for novel antibody-based Trim-Away therapeutic modalities for cancer and other diseases.