State-of-the-art small interfering RNA (siRNA) therapeutics such as givosiran 
and fitusiran are constructed from three variable components: a fully-modified 
RNA core that conveys metabolic stability, a targeting moiety that mediates 
target-cell uptake, and a linker. This structural complexity poses challenges 
for metabolite characterization and risk assessment after long-term patient 
exposure. In this study, we show that basic phosphorothioate modification of a 
siRNA targeting the oncoprotein Lin28B provides a useful increase in metabolic 
stability, without greatly compromising potency. We found that its stability in 
vitro matched that of nanoparticle-free patisiran in serum and surpassed it in 
liver tritosome extracts, although it did not reach the stability of the 
fitusiran siRNA core structure. Liver and kidney were the main sites of 
accumulation after its subcutaneous administration in mice. Despite the lack of 
a delivery agent-free antitumor effect, we anticipate our study to be a starting 
point to develop alternative siRNA scaffolds that can be degraded into 
naturally-occurring metabolites and help alleviate the aforementioned 
challenges. Furthermore, Lin28B is a promising target for cancers, and the 
development of such simplified siRNA analogs, possibly together with novel 
targeting units, holds potential.