M. Wang and P. Xu
University of South Carolina,
United States
Keywords: Protein degradation, cancer, Alzheimer's disease, antibody, pan-Trim-Away, Nano-ERASER
Summary:
Trim-Away is a versatile intracellular targeted protein degradation pathway that has been extensively explored in vitro. However, the in vivo application of Trim-Away is limited due to the lack of an in vivo practical approach for intracellular antibody delivery. Here, we developed a nanogel-based endosomal-lytic Nano-ERASER platform for the in vivo delivery of antibodies. It was revealed that Nano-ERASER can be enriched in targeted tissues and enter targeted cells, escaping from endosomes, and depleting both membrane PD-L1 in mouse models of triple-negative breast cancer and Alzheimer’s disease, and cytosolic COPZ1 in a prostate cancer model, respectively, via a TRIM21-mediated ubiquitin proteasome system pathway, thereby extending the Trim-Away effect to both membrane and cytosolic proteins. More importantly, attributed to its unique intracellular delivery design, Nano-ERASER avoids immune-related adverse effects (irAEs), which differ from those of conventional antibody-based immunotherapy. These results confirmed that Nano-ERASER achieved pan-Trim-Away in different animal disease models, which could be a safe and effective tool for degrading conventionally undruggable protein targets and for studying gene/protein function both in vitro and in vivo.