Enzyme‐Instructed Nanofibrous Assemblies Enable Targeted PROTAC Release for Cancer Therapy

Proteolysis-targeting chimeras (PROTACs) have emerged as a promising strategy for the selective degradation of oncoproteins, offering significant potential in cancer therapy, yet their clinical translation is impeded by the inherent limitations, including high hydrophobicity, poor cellular permeability, and inadequate tumor-targeting efficiency. To address these challenges, we developed a rationally engineered peptide conjugate, Nap-Lys(ARV-771)-Tyr(H₂PO₃)-Phe-Phe-OH (NapYp-ARV), to enhance the bioavailability and therapeutic efficacy of PROTACs through sequential enzyme-instructed self-assembly (EISA) and activation. Upon intratumoral phosphatase-mediated dephosphorylation, NapYp-ARV self-assembles into nanofibers that enhance tumor accumulation. Following cellular internalization, carboxylesterase-catalyzed hydrolysis liberates the PROTAC payload ARV-771, inducing potent BRD4 degradation and consequent apoptosis. In vivo, NapYp-ARV administration achieved higher tumor drug concentration than free ARV-771, driving robust protein degradation and tumor regression while maintaining hematological and histological safety. Collectively, this EISA-based delivery platform offers a versatile strategy to advance targeted PROTAC therapies.