Nanotechnology-based strategies for overcoming clinical limitations of PROTACs in cancer therapy

Proteolysis-targeting chimeras (PROTACs) have emerged as a promising next-generation therapeutic modality by enabling complete degradation of target proteins rather than transient inhibition. However, increasing clinical studies have reported adverse effects of PROTACs that resemble those observed with conventional small-molecule drugs, highlighting the need for strategies to improve tumor specificity and reduce systemic toxicity. To overcome these limitations, tumor-targeted approaches have attracted considerable attention, particularly through the development of triggered-activatable PROTACs and advanced delivery systems. In this review, we introduce recent advances in stimuli-activatable PROTACs, including those responsive to pH, enzymatic activity, and external stimuli, as well as nanotechnology-based delivery platforms such as lipid-, polymer-, albumin-, and peptide-based systems. These developments with hybrid systems are expected to facilitate the clinical translation of PROTACs by providing spatially controlled and tumor-specific therapeutic interventions.