Nanogel-facilitated Protein Intracellular Specific Degradation through Trim-Away.

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 stuck by the requirement of special skills and equipment needed for the intracellular delivery of antibodies. Hereby, an antibody conjugated polymer nanogel system, Nano-ERASER, for intracellular delivery and release of antibody, and degradation of a specific endogenous protein has been developed. After being delivered into cells, the antibody is released and forms complex with its target protein, and subsequently binds to the Fc receptor of TRIM21. The resulted complex of target protein/antibody/TRIM21 is then degraded by the proteasome. The efficacy of Nano-ERASER has been validated by depleting GFP protein in a GFP expressing cell line. Furthermore, Nano-ERASER successfully degrades COPZ1, a vital protein for cancer cells, and kills those cells while sparing normal cells. Benefit 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.