Self-Assembled Nano-PROTACs for Targeted Protein Degradation in Cancer Therapy

Proteolysis-targeting chimeras (PROTACs) induce target protein ubiquitination and proteasomal degradation via recruitment of E3 ubiquitin ligases, enabling event-driven intervention against “undruggable” targets, drug-resistant proteins, and non-catalytic scaffolding functions. Conventional PROTACs, however, face limitations including high molecular weight, poor solubility and membrane permeability, unfavorable pharmacokinetics, limited tissue selectivity, and the hook effect. Self-assembled Nano-PROTACs allow direct nanostructure formation from intact PROTACs, prodrugs, or functional modules, and permit spatiotemporal activation by tumor microenvironment or exogenous stimuli. This review systematically examines four assembly paradigms—carrier-free co-assembly, amphiphilic conjugates, peptide- and nucleic acid-programmed assembly, and split intracellular systems—and positions stimuli-responsiveness as a cross-architectural activation hallmark. Representative studies across cancer types are categorized to analyze how self-assembled Nano-PROTACs intervene in key oncogenic processes, with comparisons of target selectivity, activation mechanisms, degradation evidence, and antitumor efficacy. Finally, clinical translation requirements are discussed regarding structure–assembly–degradation relationships, safety, quality control, and scalable manufacturing, aiming to facilitate further research and clinical development of self-assembled Nano-PROTACs in cancer therapy.