Rational Design and Advanced Application of Nanoparticles in Targeted Protein Degradation.

Target protein degradation (TPD) represents an innovative therapeutic strategy with promising prospects for treating diseases driven by many undruggable protein targets. Recently, a variety of small-molecule protein degraders have shown promising therapeutic efficacy. However, several intrinsic limitations of these compounds impede their broader clinical translation. Meanwhile, advances in nanomaterials provide a versatile and powerful platform to overcome these challenges for advancing protein degradation technology. This review systematically summarizes the progress and prospects of nanoparticle-based TPD strategies. First, we critically evaluate the limitations of existing small-molecule protein degraders. We then outline the fundamental design principles that govern nano-enabled protein degradation systems and discuss how nanotechnology can address key challenges associated with delivery, selectivity, and controllability. We further highlight the distinctive properties of major nanomaterial platforms and their therapeutic applications in targeted protein degradation. Finally, we discuss the remaining obstacles and future directions for translating nano-protein degraders into clinically viable therapies. In conclusion, this review aims to provide both theoretical insights and practical guidance to propel the rational design and advanced application of TPD research.