Keywords: siRNA design, DNA basket, siRNA delivery, nanogenomics, therapeutic nanoparticles, nanotechnology, siRNA-based therapy, human diseases, peptides
Nanogenomics for medicine: emerging strategies to overcome bottlenecks in siRNA-based therapy of human diseases
Silencing of gene expression by siRNA holds a promise both for a drug target discovery and as a therapy. Major bottlenecks of siRNA technology include 'off-target' silencing effects and problems with siRNA degradation before delivery. We propose a two-fold approach aimed at curtailing described shortcomings. First, before pre-clinical tests each siRNA shall be matched to comprehensive redundancy minimiser (CRM) curated database that contain comprehensively mapped all unique sequences ('targets') 9 nt to 15 nt in size within human transcriptome. Second, we propose to deliver siRNA within DNA-wrapped RNA-containing nanoparticle formed by partial dsRNA-DNA triplex. The DNA core will be chemically modified to promote triplex formation/folding. In these binary nanoparticles, DNA will serve as the biodegradable 'basket' that could be custom designed in order to enhance its interaction with the particular siRNA duplex. We also propose to covalently bind DNA basket to targeting peptides ensuring addressed delivery of the therapeutic nanoparticle.