Abstract: Targeted protein degradation (TPD) drugs, which specifically degrade protein of interest, provide novel therapeutic strategies for a spectrum of diseases. However, traditional small-molecule degraders still face challenges such as poor bioavailability, limited availability of E3 ligases, and significant off-target effects. Macromolecule-based TPD agents, characterized by greater design flexibility and enhanced specificity, hold promise for overcoming the limitations of conventional proteolysis-targeting chimeras (PROTACs). This article focuses on macromolecular degradation systems, systematically analyzing and comparing the molecular mechanisms, clinical translation potential, and inherent challenges of different technological approaches based on two major intracellular degradation pathways—the ubiquitin-proteasome system and the lysosomal pathway. Furthermore, we discussed emerging directions, including transmembrane protein degradation and light-controlled protein degradation, offering insights for developing precision-targeted protein degradation-based therapeutic frameworks.