Nanoparticle-Mediated Targeted Protein Degradation: An Emerging Therapeutics Technology.

Targeted protein degradation (TPD) has emerged as a transformative therapeutic strategy for eliminating disease-associated proteins, with relevance across disorders ranging from cancer to neurodegeneration. Since its inception nearly two decades ago, TPD has attracted strong academic and commercial interest, with multiple candidates advancing into clinical trials. Despite this progress, the field faces persistent challenges, including limited solubility, poor cellular uptake, and unpredictable structure-activity relationship of small-molecule degraders, which complicate rational design. To address these limitations, alternative platforms such as nanoparticle-mediated protein degraders (NanoPDs) have gained attention. First reported 17 years ago, NanoPDs harness a diverse array of materials, degradation mechanisms, and linker chemistries to achieve protein clearance through novel pathways. Although promising, their clinical translation remains constrained by barriers such as lysosomal entrapment, protein corona formation, and biocompatibility concerns. In this review, we present a comprehensive overview of the current landscape of nanoparticle-mediated TPD. We emphasize the design principles underlying nano-bio interfaces and explore the role of proximity-induced biology as a mechanism for orchestrating protein interactions. Finally, we highlight critical challenges and key questions that must be addressed to fully realize the therapeutic potential of NanoPDs.