Self-assembled Nano-PROTACs: bridging chemical design and biological barriers in targeted protein degradation

Self-assembled Nano-PROTACs represent an emerging class of programmable supramolecular degraders that integrate targeted protein degradation with nanoscale delivery to overcome the intrinsic limitations of conventional PROTACs. Conventional PROTACs are often constrained by poor solubility, limited membrane permeability, suboptimal pharmacokinetics, and insufficient tissue selectivity, collectively hindering their clinical translation. Through rational engineering of polymer, peptide or aptamer conjugation, Nano-PROTACs autonomously organize into well-defined nanostructures that enhance systemic stability, circulation time, tumour accumulation, and intracellular bioavailability. These assemblies enable controlled cargo release, multivalent target engagement, and spatiotemporal precision in regulating protein degradation. In this review, we summarize the evolution of PROTAC technologies, key mechanistic and translation barriers, in addition to recent advances in Nano-PROTACs design. We further discuss therapeutic applications across oncology, immuno-modulation, neurodegenerative disorders, and metabolic diseases, highlight major challenges and future directions toward predictive design, scalable manufacturability, and clinical translation of next-generation Nano-PROTAC therapeutics.