Nanotechnology-Enabled Targeted Protein Degradation: Strategies, Opportunities, and Challenges.
Targeted protein degradation (TPD) has redefined the therapeutic landscape by shifting the focus from merely inhibiting protein function to actively eliminating disease-causing proteins. However, the clinical translation of TPD agents remains hampered by their inherent physicochemical limitations, including poor solubility, membrane impermeability, and lack of tissue selectivity. Nanotechnology offers a strategic pathway to overcome these barriers. This review examines the convergence of TPD and nanotechnology, highlighting how diverse nanoplatforms-ranging from lipid and polymeric nanoparticles to inorganic carriers and biomimetic systems-can address fundamental delivery challenges. We discuss key design strategies such as physical encapsulation, chemical conjugation, and carrier-free self-assembly between nanocarrier-assisted TPD-where nanoparticles improve degrader pharmacokinetics-and nanostructure-integrated TPD-where the nanoscaffold directly participates in ternary complex formation, and explore how engineering the nano-bio interface enables precise control over cellular uptake, intracellular trafficking, and ternary complex formation. We also critically assess current translational hurdles, including manufacturing complexity, biosafety concerns, and tumor heterogeneity, while offering perspectives on how rational design and interdisciplinary collaboration can accelerate clinical adoption. By reimagining protein degraders as components of intelligent nano-systems, nano-TPD holds the potential to transform undruggable targets into actionable therapeutic opportunities.