RNA therapeutics are of global interest
because of their versatility
in targeting a variety of intracellular and extracellular biomolecules.
In that context, long double-stranded RNA (dsRNA) has been studied
as an antitumor agent that activates the immune response. However,
its performance is constrained by poor cancer selectivity and cell-penetration
ability. Here, we designed and synthesized an oncolytic RNA hairpin
pair (oHP) that was selectively cytotoxic toward cancer
cells expressing abundant oncogenic microRNA-21 (miR-21). Although
the structure of each hairpin RNA was thermodynamically metastable,
catalytic miR-21 input triggered it to open to generate a long nicked
dsRNA. We demonstrated that oHP functioned as a cytotoxic
amplifier of information in the presence of miR-21 in various cancer
cells and tumor-bearing mice. This work represents the first example
of the use of short RNA molecules as build-up-type anticancer agents
that are triggered by an oncogenic miRNA.