Engineering Polymeric Nano-PROTAC for Targeted Protein Degradation and Cancer Therapy

Targeted protein degradation (TPD) has revolutionized the therapeutic landscape of cancer therapy. TPD aids in avoiding cellular malfunction by recruiting the protein of interest (POI) into intracellular degradation machinery. The proteolysis-targeting chimeras (PROTACs) degradation hijacks the protein's disposal system and co-opts ubiquitin E3 ligase to degrade disease-associated proteins. Numerous PROTACs have come to the forefront in cancer therapy, and several are in clinical trials. PROTACs are on the verge of U.S. Food and Drug Administration (FDA) approval. However, the low bioavailability, inadequate delivery, non-specific biodistribution, and systemic toxicity are impairing their clinical potential. Nano-PROTACs have implications for precisely targeting intractable proteins. This review provides insights into the realm of cellular mechanisms of nano-PROTACs, especially for targeting bromodomain-containing protein 4 (BRD4), programmed death-ligand 1 (PD-L1), programmed cell death protein 1 (PD-1), and indoleamine 2,3-dioxygenase (IDO). How stimuli-responsive linkages are introduced in polymeric nanoparticles to aid the controlled release of PROTACs is discussed. We provide a glimpse of how advanced polymer- and peptide-based nano-PROTACs degradation is being combined with photoimmunotherapy, radiation therapy, and chemotherapy to broaden the impact of cancer therapy. Opportunities and challenges of current strategies are discussed to preclude major limitations in clinical translation. The integration of nano-PROTACs with potentially curative therapeutic modalities may broaden the clinical performance of PROTACs.