Targeted Protein Degradation via Nanoparticles

SUMMARY Strategies that hijack selective proteins of interest (POIs) to the intracellular protein recycling machinery for targeted protein degradation (TPD) have recently emerged as powerful tools for undruggable targets in biomedical research and the pharmaceutical industry. However, targeting any new POI with current TPD tools requires laborious case-by-case design for different diseases and cell types, especially for those extracellular targets. Here, we observed that nanoparticles (NPs) can mediate the receptor-free internalization of hijacked protein and further developed a generic paradigm for both intra- and extracellular POI degradation, by making full use of clinically approved components. The phenomenon is general, as we found nanostructures such as lipid nanoparticle (LNP), liposomes, exosomes, polymeric nanoparticles, inorganic nanoparticles and their hybrid nanoparticles modified with POI-recognizing moiety (antibody, peptides, small molecule drugs) can mediate TPD for a wide range of extracellular/membrane and intracellular targets. The super flexible and feasible-to-synthesize TPD-NPs paradigm may revolutionize the current TPD tools development landscape and it provides fundamental knowledge to receptor mediated drug therapies. Highlights Nanoparticle mediated targeted protein degradation (TPD-NP) can be constructed by “Mix-and-Match” and do not require de novo synthesis or specific internalization design. TPD-NPs can be equipped with specific cell type targeting capacity, loading and controlled release of therapeutic cargos, as well as biological barrier penetration capacity. Assembling components can be clinical-approved or biodegradable for translational medicine. TPD-NP highly boosted current application platforms of nano-delivery and TPD.