Targeted protein degradation technologies: Emerging mechanisms and nano-based innovations

Targeted protein degradation (TPD) technologies have emerged as a powerful strategy for eliminating disease-causing proteins by hijacking endogenous degradation systems. Over the past decade, multiple TPD modalities—such as proteolysis-targeting chimeras (PROTACs), molecular glues, lysosome-targeting chimeras (LYTACs), autophagy-targeting chimeras (AUTACs), and others—have been developed to engage distinct cellular degradation pathways including the proteasome and lysosome systems. Despite their therapeutic promise, current TPD agents still face challenges of poor solubility, limited bioavailability, and inefficient delivery. To address these barriers, this review highlights the integration of nanotechnology with TPD as a promising approach. We summarize recent progress in proteasome- and lysosome-directed TPD strategies and describe how nanomaterials—including liposomes, polymers, inorganic nanoparticles, carbon dots, and ferritin—are applied to construct multivalent degraders, enhance pharmacokinetics, and demonstrate synergistic efficacy when combined with chemotherapy, immunotherapy, or catalytic therapies. In addition, we discuss the emerging convergence of nanozymes with TPD, where catalytic generation of reactive oxygen species not only regulates ubiquitination–deubiquitination balance but also facilitates endosomal disruption and boosts therapeutic efficacy. By bridging mechanistic innovation with nano-enabled platforms, nano-based TPD technologies offer enhanced precision, safety, and multifunctionality. Their continued advancement is poised to accelerate clinical translation and reshape strategies for treating complex and previously intractable diseases.