The Merkel lab focuses on novel non-viral and targeted nanosized siRNA delivery systems. We are especially interested in theragnostic pulmonary delivery of siRNA with an emphasis on cancer immunology and immunologic diseases of the lung, like allergic asthma.

In 2006, Andrew Fire and Greg Mello were awarded the Nobel Prize in Physiology for their discovery of gene silencing by introduction of double-stranded RNA (dsRNA) (1). Their work led to the identification of a catalytic mechanism of a multi-protein complex (2) which incorporates short RNAs that on their part are complementary in sequence to mRNA which is subsequently degraded (1). This mechanism which is an evolutionary conserved defense process for inactivation of foreign, e.g. transposable, viral or bacterial genetic information (3, 4), can also be exploited biotechnologically. Long dsRNA which naturally or directedly reach the cytoplasm are degraded by “Dicer”, an RNase III-like enzyme, into small interfering RNAs (siRNAs) of 21 to 25 nucleotides in length (5). While long dsRNA can interact with Toll-like receptor 3 (TLR3) (6), synthetic short interfering RNA (siRNA) no longer than 19-21 base pairs with 2 nt 3’ overhangs is efficient (7, 8) and lacks interferon response (9). After being transferred into the cytosol, where it is incorporated into the RNA-induced silencing complex (RISC), double-stranded siRNA is cleaved upon activation of RISC, and complementary mRNA can bind to the antisense strand. Argonaute (Ago2), an endonuclease in the RISC, subsequently cleaves the mRNA leading to down-regulation of the target gene expression.