Engineering Lipid-Mediated Delivery of Recombinant bioPROTACs for Efficient Intracellular Protein Degradation

Lipid-mediated intracellular delivery of recombinant #bioPROTACs for rapid degradation of #undruggableproteins has recently gained prominence in targeted degradation therapy. Utilizing 'event-driven' pharmacology, #proteolysistargetingchimeras (#PROTACs) offer superior efficacy compared to traditional inhibitors against challenging targets. However, their development is hindered by limited availability of suitable warheads and intensive optimization processes. To overcome these challenges, #bioPROTACs, protein-based heterobifunctional degraders, have been engineered. Unlike small-molecule PROTACs, #bioPROTACs exhibit higher success rates and fewer design constraints. Yet, their therapeutic applicability is limited by poor membrane permeability. This study introduces an engineered bioPROTAC template capable of forming complexes with cationic and ionizable lipids through electrostatic interactions, facilitating cytosolic delivery. When delivered via biocompatible lipid nanoparticles (#LNPs), these modified bioPROTACs demonstrate rapid intracellular protein degradation, achieving nearly complete clearance (up to 95%) of target proteins within hours of treatment. This approach effectively targets proteins localized in various subcellular compartments such as mitochondria, nucleus, cytosol, and membranes. Moreover, the substrate specificity can be easily reprogrammed, enabling tailored design and targeting of clinically significant proteins like Ras, Jnk, and Erk. In summary, this work presents a cost-effective, adaptable, and scalable platform for efficient intracellular protein degradation, offering potential solutions where chemical inhibition falls short.

Chan, A., Haley, R.M., Najar, M.A. et al. Lipid-mediated intracellular delivery of recombinant bioPROTACs for the rapid degradation of undruggable proteins. Nat Commun 15, 5808 (2024). https://doi.org/10.1038/s41467-024-50235-x