Advances in nanoparticle delivery systems for enhanced PROTAC therapy of breast cancer

Breast cancer remains one of the most prevalent malignancies worldwide, with approximately 2.3 million new cases and 670 000 deaths reported globally in 2022. Current therapeutic challenges include the difficulty in targeting breast cancer-associated proteins lacking active sites through traditional small-molecule inhibitors, as well as the high incidence of acquired drug resistance, which collectively undermine treatment outcomes. The advent of proteolysis-targeting chimera (PROTAC) technology has provided a solution, offering a unique protein degradation mechanism to circumvent these limitations. Nevertheless, clinical translation of PROTACs requires addressing inherent limitations such as poor solubility, low bioavailability, and insufficient targeting specificity. To overcome these barriers, multifunctional nano-delivery systems have emerged as a promising technological platform to enhance the therapeutic potential of PROTACs. This review systematically examines the latest advances in nanotechnology-enabled PROTAC delivery for breast cancer treatment, with particular emphasizes rational nanocarrier design principles and synergistic mechanisms of antitumor combination therapies. We further critically analyze persistent translational challenges and propose forward-looking solutions. The integration of nanotechnology with PROTACs not only overcomes the limitations of traditional therapies but also offers new insights into the precise treatment of breast cancer.