Nanoenabled Strategies Enhancing PROTACs for Cancer Therapy

Proteolysis-targeting chimeras (PROTACs) have emerged as a breakthrough therapeutic strategy in oncology, enabling the selective degradation of traditionally “undruggable” proteins via the ubiquitin-proteasome system. However, their clinical translation remains challenging due to high molecular weight, limited aqueous solubility, and metabolic instability, which limit systemic bioavailability and tumor penetration. To address these challenges, a variety of nanocarrier systems have been developed to improve the stability, pharmacokinetics, and tumor-specific accumulation of PROTACs. Beyond delivery enhancement, nanotechnology also enables the creation of next-generation PROTAC modalities, such as mRNA-encoded and RNA-scaffolded PROTACs, thereby expanding their therapeutic potential. In parallel, stimuli-responsive nanocarriers offer spatiotemporal control over PROTAC release, maximizing therapeutic efficacy while minimizing off-target effects. This review provides a comprehensive overview of nanotechnology-enabled strategies for PROTAC delivery, highlights key translational challenges, and discusses future directions to facilitate their clinical advancement in cancer therapy.