Active targeting strategies for PROTAC delivery in cancer therapy: Advances, challenges, and future perspectives

Proteolysis-targeting chimeras (PROTACs) have emerged as a promising therapeutic modality for cancer treatment; however, their clinical translation remains hindered by unfavorable pharmacokinetic properties, limited tumor selectivity, and systemic toxicity. This review provides a comprehensive overview of targeted drug delivery strategies developed to enhance the delivery efficiency and therapeutic selectivity of PROTAC-based agents. We summarize recent advances in ligand-mediated approaches, including aptamer-, antibody-, peptide-, and small-molecule-based PROTAC conjugates, as well as ligand-modified nanoparticle systems and chemically engineered strategies that enhance receptor-mediated cellular uptake, such as CD36-dependent endocytosis. Finally, we critically evaluate key translational challenges associated with targeted PROTAC delivery, including receptor heterogeneity and internalization efficiency, endosomal escape, tumor penetration, release control, manufacturing complexity, scalability, and safety considerations. We further establish a unified mechanism-level comparative framework that systematically assesses each delivery modality across seven dimensions and discuss the architectural divide between cytosol-directed and membrane-directed platforms, the current clinical translation status, and practical design principles to support the rational development of PROTAC-based cancer therapeutics.