A Universal Protein Tag for Delivery of SiRNA-Aptamer Chimeras

Liu, Hong Yan; Gao, Xiaohu

Discussion siRNA-aptamer chimera is one of the most promising approaches for cell type-specific RNAi, owing to its low immunogenicity, ease of chemical synthesis and modification, small size, and the modularity of both the targeting aptamer block and the therapeutic siRNA segment. More importantly, employing only RNA molecules, the simple formulation of chimera-based targeted siRNA therapy leads to outstanding clinical translation 15, 16 . Due to the incapability of chimera to efficiently escape endosome, delivery nanocarriers are needed. However, almost all current targeted siRNA delivery formulations involve cationic nanocarriers such as polymers, inorganic nanoparticles, peptides, and proteins 7, 19, 20, 27, 28, [38] [39] [40] [41] [42] [43] [44] . Unfortunately, these conventional siRNA nanocarriers are unsuitable for chimera delivery, and, in fact, reverse the signature property of chimera, simple formulation for regulatory approval and clinical translation 15, 16 . This is because the charge induced complex formation is basically an aggregation process, which lacks control over aggregate size, shape, stoichiometry, chimera orientation, aptamer functionality, and reproducibility during scale-up production. In addition, the final complexes often carriers positive charges as well, which is unfavorable for systemic uses 23 . As a result, first clinical trials of siRNA duplexes are mainly limited to local administrations [45] [46] [47] [48] .