NanoTAC in targeted protein degradation: Intelligent delivery platforms and synergistic therapeutic paradigms

Targeted protein degradation (TPD) has reshaped therapeutic strategy by catalytically eliminating pathogenic proteins through engagement with endogenous proteolytic systems. In contrast to conventional inhibitors that transiently block enzymatic activity, TPD achieves durable target silencing by physically removing the protein entirely, thereby overcoming resistance mechanisms and extending therapeutic durability. This approach enables the pharmacological modulation of previously "undruggable" entities, such as transcription factors and scaffolding proteins, that lack canonical binding pockets. However, clinical translation of existing TPD platforms, including PROTACs and molecular glues, remains limited by poor bioavailability, off-target toxicity, and suboptimal tissue selectivity. Nanoparticle-assisted targeted protein degraders (NanoTACs) offer a compelling solution by coupling the catalytic efficiency of TPD with the spatial precision and tunability of nanotechnology. Through rational nanocarrier engineering, NanoTACs overcome key limitations of small-molecule degraders, including poor solubility, rapid systemic clearance, and inadequate targetability, while enabling direct and selective degradation of pathogenic proteins with minimal structural modification. This integration affords programmable control of biodistribution, cellular uptake, and release kinetics, as well as microenvironment-responsive degradation that is difficult to achieve with traditional modalities. Beyond functioning as delivery vehicles, NanoTACs actively recruit degradation machinery, modulate intracellular proteostasis, and permit synergistic co-delivery of therapeutic payloads. Emerging data demonstrate their capacity to degrade oncogenic drivers, suppress inflammatory signaling, and eliminate pathological protein aggregates across diverse disease models. This Review delineates the conceptual foundations, design principles, and translational prospects of NanoTACs, positioning them as a next-generation platform at the intersection of nanomedicine, chemical biology, and precision oncology.