Nanosized Multifunctional Polyplexes for Receptor-Mediated SiRNA Delivery

Although our understanding of RNAi and our knowledge on designing and synthesizing active and safe siRNAs significantly increased during the past decade, targeted delivery remains the major limitation in the development of siRNA therapeutics. On one hand, practical considerations dictate robust chemistry reproducibly providing precise carrier molecules. On the other hand, the multistep delivery process requires dynamic multifunctional carriers of substantial complexity. We present a monodisperse and multifunctional carrier system, synthesized by solid phase supported chemistry, for siRNA delivery <i>in vitro</i> and <i>in vivo</i>. The sequence-defined assembly includes a precise cationic (oligoethanamino)amide core, terminated at the ends by two cysteines for bioreversible polyplex stabilization, at a defined central position attached to a monodisperse polyethylene glycol chain coupled to a terminal folic acid as cell targeting ligand. Complexation with an endosomolytic influenza peptide-siRNA conjugate results in nanosized functional polyplexes of 6 nm hydrodynamic diameter. The necessity of each functional substructure of the carrier system for a specific and efficient gene silencing was confirmed. The nanosized polyplexes showed stability <i>in vivo</i>, receptor-specific cell targeting, and silencing of the EG5 gene in receptor-positive tumors. The nanosized appearance of these particles can be precisely controlled by the oligomer design (from 5.8 to 8.8 nm diameter). A complete surface charge shielding together with the high stability result in good tolerability <i>in vivo</i> and the absence of accumulation in nontargeted tissues such as liver, lung, or spleen. Due to their small size, siRNA polyplexes are efficiently cleared by the kidney

Literature search scheme.

<p>Literature search scheme.</p

The quality analysis of all 6 studies.

<p>(A) Summary of the risk of bias in all included 6 studies. (B) Risk of bias graph: judgements about each risk of bias item presented as percentages across all included 6 studies.</p

Publication bias assessment of this meta-analysis.

<p>Publication bias assessment of this meta-analysis.</p

Summary of pooled data comparing preventive antibiotic group and control group in adult patients with acute stroke.

<p>Summary of pooled data comparing preventive antibiotic group and control group in adult patients with acute stroke.</p

The characteristics of the six included studies.

<p>The characteristics of the six included studies.</p