Teaching old proteins new tricks
A natural protein-based, non-cationic nanocarrier for efficient siRNA delivery
The paper in Nature Biomedical Engineering is here: https://go.nature.com/2GAhMrU
The Nobel prize-winning RNAi technology can mediate potent, target-specific knockdown of virtually any mRNA, creating a useful and proven genetic surrogate tool. Unfortunately, the clinical translation and commercialization of this technology have experienced setbacks due to inefficient delivery, the same old problem that have plagued the development of all previous antisense approaches and which may impact future genomic tools such as gene editing. A large number of nanocarriers, such as liposomes, polymers, peptides, and inorganic nanoparticles, have been developed previously, but their efficiency for in vivo cell-type specific delivery was low. The problem for delivery vehicle design is the conflicting requirements of using cationic materials for cargo condensation and endosomolysis while avoiding cationic materials for in vivo targeting and colloidal stability.
Because of this fundamental conflict, we decided to step away from fine tweaking the conventional cationic liposomes and polymers. Instead, we explored a new strategy based on molecular engineering of natural proteins. Nature ultimately optimized transporters for sustained and on-demand delivery of a large variety of compounds including small molecules, macromolecules, nutrients, oxygen, as well as wastes. In our paper just published in Nature Biomedical Engineering, we explored millions of years of natural evolution and picked functional building blocks from the human proteome, such as RNA binding domains (dsRBD) for siRNA binding in the current paper.
For tricks that natural proteins don’t have, such as endosomal disruption, non-natural peptides were added to the overall architecture, and they were added in specific way. To avoid potential immune responses (e.g. recognition by antibodies), the non-natural peptides were embedded in the protein core. Based on this idea, a model ribonucleoprotein octamer (Figure 1) with all the desired features such as compact size, high payload, absence of cationic surface charge, colloidal stability, binding specificity, and biocompatibility, was constructed and applied to cancer therapy.
Figure 1. Schematic illustration of ribonucleoprotein octamer.
Conceptually, rational design and intelligent integration of functional protein building blocks lead to production of a broad spectrum of delivery vehicles with unprecedented efficiency and therapeutic efficacy. Technically, precisely engineered molecular architectures have come of age enabled by nanotechnology and molecular cloning.
Our paper: Tai, W. et al. A ribonucleoprotein octamer for targeted siRNA delivery. Nat. Biomed. Eng. doi:10.1038/s41551-018-0214-1.