Small RNA stabilization via non-covalent binding with a metalloporphyrin nanocage to accomplish synergistic gene and photodynamic therapy

Small RNAs (sRNAs) have emerged as attractive therapeutic agents due to their gene-editing and -regulatory properties. However, their application is severely limited by their relatively short circulation half-lives. Herein, we report a strategy binding sRNA with metalloporphyrin cages that leads to a significant protection of sRNA against RNase degradation and increased half-lives. Nuclear magnetic resonance (NMR) titration of nucleosides and nucleotides demonstrates that π-stacking and electrostatic interactions contribute to the sRNA binding, which occurs on the external surface of the nanocage. Moreover, the cage binding promotes sRNA internalization, and the sRNAs maintain genetic activity after release in an acidic intracellular environment. Taking advantage of the photodynamic properties of the cage, the nanosystem shows efficient in vitro cell killing through gene regulation and photodynamic effects, providing evidence for its therapeutic potential in breast cancer treatment. We envision the proposed strategy may provide new insight for the development of organometallic cage-based sRNA delivery vehicles. [Display omitted] •Small RNAs efficiently bind to metalloporphyrin cages via non-covalent interactions•Strong binding significantly enhances the small RNA human serum stability•The platform is used for synergistic gene regulation and photodynamic therapy Small RNAs are regarded as attractive therapeutic agents, but biodegradation severely limits their application. Herein, Weiguang et al. report on small RNAs binding to metalloporphyrin cages, significantly protecting RNA against degradation and facilitating synergistic gene regulation and photodynamic therapy for killing breast cancer cells.