Enzyme-Instructed Nanofibrous Assemblies Enable Targeted PROTAC Release for Cancer Therapy.

Area of Science:

• Biochemistry
• Molecular Biology
• Drug Delivery Systems

Background:

• Proteolysis-targeting chimeras (PROTACs) show promise for cancer therapy but face challenges like poor bioavailability and tumor targeting.
• Limitations include hydrophobicity, poor cell permeability, and inefficient tumor accumulation.

Purpose of the Study:

• To develop an engineered peptide conjugate (NapYp-ARV) to overcome PROTAC limitations.
• To enhance PROTAC bioavailability and therapeutic efficacy using enzyme-instructed self-assembly (EISA) and activation.

Main Methods:

• Designed NapYp-ARV, a peptide conjugate utilizing sequential EISA and activation.
• Investigated phosphatase-mediated dephosphorylation for self-assembly into tumor-accumulating nanofibers.
• Assessed carboxylesterase-catalyzed hydrolysis for PROTAC payload release and BRD4 degradation.

Main Results:

• NapYp-ARV self-assembled into nanofibers upon dephosphorylation, enhancing tumor accumulation.
• Intracellular hydrolysis released the PROTAC payload, inducing BRD4 degradation and apoptosis.
• In vivo studies showed increased tumor drug concentration, robust protein degradation, and tumor regression with good safety.

Conclusions:

• The EISA-based delivery platform effectively enhances PROTAC bioavailability and tumor targeting.
• This strategy offers a versatile approach to advance targeted PROTAC therapies for cancer.
• NapYp-ARV demonstrates significant potential for improving cancer treatment outcomes.