Spatiotemporal control of protein degradation: Advances in stimuli-responsive nano-PROTACs for precision cancer therapy

Proteolysis-targeting chimeras (PROTACs) have shown great promise in recent years as a new class of drugs capable of targeting and degrading difficult-to-treat proteins. However, the clinical translation of PROTACs is hindered by their unfavorable physicochemical characteristics (e.g., high molecular weight, poor solubility) and the potential for systemic off-target toxicity due to the widespread expression of E3 ligases. To address these issues, stimuli-responsive nano-PROTACs have been developed to enable spatiotemporal control over PROTAC activation. This review critically discusses the development of nano-PROTACs and summarizes different design strategies, including early passive encapsulation and more advanced stimuli-responsive nanostructures activated by endogenous signals (e.g., pH, enzymes and redox conditions) and exogenous signals (e.g., light and ultrasound). The emerging trend of dual-response “Logic Gate” systems and carrier-free poly-PROTAC paradigms is also presented. The review also discusses the combination of nano-PROTACs with other therapeutic strategies to maximize therapeutic efficacy and minimize drug resistance, a critical aspect for clinical applications. Finally, future prospects for nano-PROTACs are introduced, with the expectation that research in this field will continue to progress. Based on the above analysis of these technological developments, the remaining challenges and possible countermeasures for achieving precise protein degradation in clinical practice can be identified.