Nano-PROTACs for precision medicine: engineering strategies for enhanced targeting and potency

Proteolysis-targeting chimeras (PROTACs) represent a transformative therapeutic modality that leverages the endogenous ubiquitin-proteasome system (UPS) to achieve targeted protein degradation. These heterobifunctional molecules facilitate the recruitment of E3 ubiquitin ligases to a protein of interest (POI), promoting its ubiquitination and subsequent proteasomal degradation. In contrast to conventional inhibitory approaches, PROTACs operate catalytically, enabling the degradation of a wide spectrum of targets-including those harboring drug-resistant mutations-at significantly lower doses. These attributes have positioned PROTACs as promising agents, particularly in oncology, where their efficiency and broad applicability have been increasingly demonstrated. Nonetheless, clinical translation of PROTACs faces challenges such as poor bioavailability, insufficient tumor-specific accumulation, and off-target effects. The integration of nanomedicine-based delivery platforms offers a viable path to overcome these limitations by enhancing drug stability, improving tissue selectivity, and reducing systemic toxicity. This review outlines the rational design principles underlying nano-PROTACs, highlights recent advances in nanoformulations aimed at optimizing their delivery and efficacy, discusses emerging combination regimens and innovative design strategies, and critically assesses the translational challenges and future directions of nano-PROTACs. Overall, nano-PROTAC technology has pioneered a brand-new approach in the field of disease treatment, providing unprecedented opportunities for precision medicine and personalized disease treatment.