Extracellular HSP90-Facilitated Degradation of Extracellular and Membrane Proteins by Bifunctional Small Molecules

Lysosome-targeting chimeras represent a promising strategy for degrading extracellular and membrane proteins via the lysosomal pathway, but the available receptor options remain limited. Herein, we report a novel strategy utilizing extracellular heat shock protein 90 (eHSP90) to facilitate lysosomal degradation of target proteins through bifunctional small molecules, termed extracellular heat shock protein 90-targeting chimeras (eHSPTACs). By connecting an HSP90 ligand to a target protein ligand, eHSPTACs effectively induced the internalization and subsequent lysosomal degradation of extracellular Alexa Fluor 488-labeled α-DNP antibody and membrane programmed cell death-ligand 1 (PD-L1). Notably, <b>dPDL1-4</b> selectively degraded membrane PD-L1 in tumor cells over normal cells, leveraging the elevated expression of eHSP90 in cancer cells. Moreover, <b>dPDL1-4</b> demonstrated robust in vivo degradation of membrane PD-L1 and significant tumor growth suppression in the B16F10 syngeneic mouse model. Overall, eHSPTACs offer a general platform for tumor-selective degradation of extracellular and membrane proteins, providing a new therapeutic avenue.