Molecular Engineering of Stimuli-Activatable Protein Degraders for Precise Cancer Therapy

The emerging advance of targeted protein degradation (TPD) technology offers a novel option for protein modulation, ensuring a more durable and precise therapeutic impact for cancer management. While promising, complete degradation of the proteins of interest (POIs) in both pathological and normal tissues may cause severe side effects. Furthermore, insufficient accumulation of the protein degraders at the target tissues also limits the clinical translation of TPD. It remains an unmet need to achieve spatiotemporally tunable degradation of the POI at the tumor lesion. In recent years, our group has extensively exploited the potential of the stimuli-activatable TPD technology for precise cancer therapy. The stimuli-activatable protein degraders were rationally designed for achieving tumor-specific enrichment in vivo to maximize their therapeutic effects while minimizing the side effects. Several kinds of stimuli-labile prodrugs of the proteolysis targeting chimeras (PROTACs) were rationally designed for restoring their protein degradation functions with the endogenous or exogenous stimulus of tumor while remaining "silent" elsewhere, resulting in precise therapies and reduced side effects. Leveraging the advantages of nanomedicine delivery systems, several kinds of tumor acidity and enzymatic-activatable nanodegraders were developed to achieve tumor-targeted protein degrader distribution and POI degradation. In particular, photothermally activatable protein degraders were developed to perform spatiotemporally controllable degradation of various POIs. In this Account, we systematically summarize recent advances from our group regarding the rational design of stimuli-activatable protein degraders, and strategically outline the "when and how" of integrating these degraders with nanomedicine platforms to tailor precise cancer therapy. We discuss the crucial role of the tumor microenvironment-responsive moieties for stimuli-triggered degradation of both intracellular and membrane POIs, highlighting the distinct design rationale for their respective prodrugs. Furthermore, we summarize our advances of strategic integration of the TPD technology with nanomedicine to augment the therapeutic outcomes of phototherapy, radiotherapy, chemotherapy, and immunotherapy of solid tumors. It is envisaged that the tumor microenvironment-activatable protein degradation approaches will achieve tumor-specific protein degradation and precision therapy, thereby facilitating the clinical application of TPD. By outlining optimized design strategies and future challenges, this Account aims to serve as a roadmap for researchers seeking to develop next-generation activatable TPD technologies that are modular, functionally versatile, and translatable.