Nanoparticle-Based Delivery Strategies for Targeted Protein Degradation

Targeted protein degradation (TPD) has fundamentally redefined pharmacological intervention, shifting from classical occupancy-driven inhibition to event-driven elimination of undruggable pathogenic proteins, holding great promise for treating various intractable diseases. Although heterobifunctional degraders and molecular glues show immense therapeutic promise, their clinical translation is hindered by pharmacokinetic and pharmacodynamic disconnects, including violation of Lipinski's Rule of Five (Ro5) and autoinhibitory thermodynamics known as the hook effect. Nanoparticle-based delivery systems offer a feasible solution that goes beyond passive solubilization. This review provides a comprehensive evaluation of advanced nanocarriers as spatiotemporal kinetic orchestrators, highlighting their capacity for active and precise therapeutic applications. In this review, we summarize recent progress in nanoparticle-based TPD delivery strategies, outlining TPD molecular pathways and diverse nanocarriers for efficient delivery of TPD agents, including liposomes, polymeric nanoparticles, micelles, DNA nanostructures, inorganic nanomaterials, and biological carriers. Furthermore, the mechanisms, targeting strategies, preclinical efficacy, biological barriers, and optimization strategies of these works are detailed. Finally, we propose two solutions, namely localized zero-order release platforms and engineered living vectors, with the potential to bypass physiological barriers and promote the clinical translation of TPD.