In situ self-assembly of PROTACs for precision cancer therapy

Proteolysis-targeting chimeras (PROTACs) are heterobifunctional molecules that degrade pathogenic proteins via the ubiquitin-proteasome system. Their event-driven mechanism enables targeting of traditionally undruggable proteins and overcomes acquired resistance through complete protein degradation. Despite these advantages in cancer therapy, clinical translation of PROTACs is hampered by high molecular weight, poor solubility, off-target effects, and the hook effect. To address these challenges, integrating bioorthogonal in situ self-assembly of PROTACs with advanced nanodelivery platforms has emerged as a promising strategy to enhance delivery efficiency, enable spatiotemporally controlled protein degradation, and reduce toxicity. This review systematically outlines design and construction strategies for in situ self-assembling PROTACs, highlighting recent advances in nanodelivery systems that improve solubility, bioavailability, and degradation efficacy while mitigating off-target effects and the hook effect. Finally, we discuss current challenges and future perspectives for PROTACs-based precision cancer therapy.