Targeted protein degradation (TPD) offers a revolutionary paradigm to eliminate disease-driving proteins. Given the distinct technical requirements and challenges associated with degrading intracellular versus extracellular proteins, we classify existing TPD strategies based on subcellular localization into two categories: intracellular TPD (iTPD), which targets proteins within the cytoplasm and nucleus, and extracellular TPD (eTPD), which focuses on membrane-bound and secreted proteins. This destination-based framework facilitates precise technology selection and rational design by aligning methods with the biological context of their targets. However, the clinical translation of TPD remains constrained by a significant “delivery gap”. Current nanotechnological approaches are often discussed monolithically, despite the fundamentally distinct delivery requirements between iTPD and eTPD. For iTPD, the primary nanocarrier role is to confer fundamental drug-like properties to overcome systemic pharmacokinetic hurdles. Conversely, for eTPD, the nanoplatform's chief function is to engineer cellular engagement, enhance internalization, and orchestrate correct intracellular trafficking to the lysosome. This review will dissect the distinct challenges inherent to each “geographic” space and detail the tailored nano-playbooks being developed to address them. We will further explore the convergence of these two worlds and the emergence of nanoparticles as intrinsic degraders. Ultimately, we argue that a location-aware design philosophy is essential for unlocking the full therapeutic potential of TPD.

Drug delivery system  /  Nanoplatform  /  Targeted protein degradation (TPD)  /  Proteostasis  /  Lysosomal degradation  /  Proteasomal degradation  /  Intracellular protein degradation  /  Extracellular protein degradation