New-generation advanced Nano-PROTACs as potential therapeutic agents in cancer therapy

Proteolysis targeting chimeras (PROTACs) are catalytic degraders that eliminate pathogenic proteins via the ubiquitin-proteasome system (UPS). Building on this mechanism, nano-engineered PROTACs (Nano-PROTACs) integrate PROTACs with rationally designed nanomaterials to create an emerging therapeutic platform for cancer. This integrative approach preserves the core capability of PROTACs to precisely degrade pathogenic proteins through the UPS, and also confers multiple therapeutic advantages including enhanced tissue targeting, improved membrane permeability, and controlled drug release, thereby significantly improving cancer therapeutic efficacy while effectively reducing systemic toxicity. This review provides a comprehensive overview of recent advances in Nano-PROTACs for cancer therapy, with a particular focus on the design strategies enabled by nanomaterial-based delivery systems, along with the applications in monotherapy and synergistic therapies. In addition, the therapeutic advantages and existing challenges of Nano-PROTACs are critically discussed, while delineating their potential future clinical applications, providing critical insights to the understanding of this emerging technology and offering novel perspectives for future development of precision therapeutics.