Revolutionizing protein degradation: Harnessing nanoparticles for PROTAC delivery

Proteolysis-targeting chimera (PROTAC) represents a paradigm shift in drug discovery, offering a promising therapeutic strategy for cancers, neurodegenerative diseases, and hematological malignancies. Unlike traditional small-molecule inhibitors that require occupancy of an active site, PROTAC operates via an event-driven mechanism, hijacking the ubiquitin-proteasome system to degrade target proteins. This approach can potentially convert "undruggable" targets into tractable ones, dramatically expanding the druggable proteome. However, the clinical translation of PROTAC faces a significant bottleneck due to inherent physicochemical and pharmacokinetic challenges, including poor solubility, limited membrane permeability, and off-target effects. Nanomedicine delivery systems have emerged as a powerful platform to overcome these hurdles. By encapsulating or conjugating PROTAC, nanocarriers can enhance bioavailability, improve cellular delivery, and increase target specificity, thereby unlocking their full therapeutic potential. This review systematically examines recent advances in nanoparticle-based PROTAC delivery. We illustrate how nanocarrier design-spanning organic, inorganic, biomimetic, and prodrug platforms-can optimize PROTAC properties and enhance therapeutic outcomes. Furthermore, we analyze current limitations and outline future directions to guide the development of next-generation delivery strategies, with the ultimate goal of accelerating the clinical translation of these transformative agents.