Polymeric Lysosome-Targeting Chimeras (PolyTACs): Extracellular Targeted Protein Degradation without Co-Opting Lysosome-Targeting Receptors.

Extracellular targeted protein degradation (eTPD) is an emerging modality to regulate protein levels without genomic interruption. Current strategies co-opt lysosome-targeting receptors (LTRs) that are ubiquitously present in most cells, offering a high success rate of eTPD across cell types and tissues. To circumvent on-target, off-site protein degradation, exploring alternative strategies is becoming a main focus to advance conventional platforms. Until now, many efforts have been focused on developing degraders by repurposing the surface receptors with intrinsically internalizing function. Yet, exploring novel access to eTPD would introduce an arguably nimble molecular design paradigm that opens up new opportunities in many diseases without such receptor availability. Opening up the binding complementarity requirement from LTRs to any overexpressed cell surface receptor offers to endow eTPD platforms with new cellular targeting capabilities. Here, we report polymeric lysosome-targeting chimeras (PolyTACs), a polymer-antibody conjugate based platform for the targeted degradation of membrane-bound and soluble proteins without the need for involving LTRs. Mechanistic investigations suggest a nonclassical uptake pathway caused by the multivalent interactions between the PolyTACs and the overexpressed functionalities on the cell surface. The utility of PolyTACs in eTPD has been demonstrated with four disease-relevant membrane proteins. Additionally, the same design principle has also been leveraged to bind and drag soluble extracellular proteins into the lysosome. The design and fabrication simplicity, nonreliance on LTRs, and tissue-targeting capabilities open up new avenues for eTPD in many disease-specific applications.