• • PROTACs exhibit high molecular weight and poor bioavailability, which limit passive tumor accumulation; nanoencapsulation addresses these by improving solubility and stability, potentially increasing intratumoral drug exposure by orders of magnitude compared to free PROTACs.
• • Nanocarriers enable spatiotemporally controlled release via passive (EPR effect) or active targeting, reducing systemic toxicity; this is critical because off-tumor PROTAC activity can degrade healthy tissue proteins, leading to dose-limiting toxicities.
• • The integration of PROTACs with nanotechnology facilitates synergistic combination therapies, e.g., with radiotherapy or immunotherapy, potentially overcoming acquired resistance mechanisms such as target mutation and pathway rewiring.
• • Clinical translation of nano-PROTACs faces scalability and manufacturing challenges, including batch-to-batch reproducibility and long-term stability; however, the platform's modularity supports personalized targeting ligands, aligning with precision oncology paradigms.