Engineering Multifunctional Nano-PROTACs Platforms for Precision Cancer Therapy
Conventional cancer therapies remain constrained by undruggable oncogenic proteins and acquired resistance. Proteolysis targeting chimeras (PROTACs) have emerged as a transformative modality that harnesses the ubiquitin-proteasome system to selectively degrade target proteins, offering advantages over traditional small-molecule inhibitors. However, clinical translation of PROTACs is impeded by intrinsic physicochemical limitations: high molecular weight, poor bioavailability, and lack of tumor-specific delivery. Integrating PROTACs with nanotechnology has yielded advanced nano-PROTACs platforms. Nanocarriers enhance solubility and stability, optimize pharmacokinetics, and enable spatiotemporally controlled drug release through passive or active targeting. This review systematically summarizes recent advances in engineering multifunctional nano-PROTACs for cancer therapy, with particular emphasis on design strategies by which nanoengineering enhances PROTAC performance. We evaluate how these platforms improve anticancer efficacy and minimize systemic toxicity while exploring their therapeutic potential in monotherapy and synergistic treatment settings. Finally, we discuss current challenges and future perspectives, providing a theoretical and technical foundation for next-generation nano-PROTACs as a precise and potent strategy in precision oncology.