An Enzyme-Catalyzed Polymerization Strategy Disrupts Protein Homeostasis for Improved Tumor Therapy

Proteins are essential components within living cells, playing crucial roles necessary for organismal function and maintaining cellular homeostasis. Dysregulated proteostasis is associated with tumorigenesis and cancer progression. Therefore, the regulation of cellular protein homeostasis in tumor cells provides novel therapeutic directions for cancer treatment. We herein report an enzyme-catalyzed polymerization strategy to disrupt tumor protein homeostasis, which specifically induces the overaccumulation of misfolded proteins in melanoma cells. The system comprises a tyrosinase-catalyzed peptide fragment, which conjugates to the proteasome inhibitor bortezomib via pH-responsive phenylboronate linkage, enabling controlled release within the acidic lysosome environment of tumor cells. The tyrosine-catalyzed polymerization process covalently binds proteins to generate excess misfolded proteins. Meanwhile, bortezomib inhibits proteasome activity and promotes the overaccumulation of misfolded proteins, which triggers endoplasmic reticulum stress and apoptotic pathway activation. Disruption of the proteostasis provides a new strategy to specifically regulate overaccumulation of misfolded proteins for cancer therapy.