Conditionally\nActivatable Chimeras for Tumor-Specific\nMembrane Protein Degradation

The\nrecent advancements on membrane protein degraders (MPDs) have\nbroadened the applicability of proteolysis-targeting chimeras (PROTACs)\nbeyond intracellular proteins to include the previously “undruggable”\ncell-surface targets. However, the potential toxicity of MPDs caused\nby undesired off-target degradation poses a significant challenge\nto clinical deployment, mirroring concerns associated with PROTACs.\nHere, we introduce a conditionally activatable membrane protein degrader\n(Pro-MPD), which leverages the specificity and high affinity of biparatopic\nnanobodies combined with a tumor microenvironment-activated cell-penetrating\npeptide (Pro-CPP) to achieve on-target activated internalization and\ndegradation of PD-L1 within tumor sites. This modularly designed Pro-MPD\ndemonstrated a high target degradation efficiency and T cell reactivation,\nas well as sustained inhibition of tumor growth in xenograft models,\nhighlighting its potential as a safer and highly efficient MPD for <i>in vivo</i> applications. Our work provides a general strategy\nfor the development of conditionally activatable MPDs, which offers\na new avenue for reducing the undesired systemic toxicity of MPDs\ndue to the off-tumor degradation.