RNA Nanotechnology to Solubilize Hydrophobic Antitumor Drug for Targeted Delivery

Small‐molecule drugs are used extensively in clinics for cancer treatment; however, many antitumor chemical drugs dissolve poorly in aqueous solution. Their poor solubility and nonselective delivery in vivo often cause severe side effects. Here, the application of RNA nanotechnology to enhance the solubility of hydrophobic drugs, using camptothecin (CPT) for proof‐of‐concept in targeted delivery for cancer treatment is reported. Multiple CPT prodrug molecules are conjugated to RNA oligos via a click reaction, and the resulting CPT‐RNA conjugates efficiently self‐assemble into thermodynamically stable RNA three‐way junction (3WJ) nanoparticles. The RNA 3WJ is covalently linked with seven hydrophobic CPT prodrug molecules through cleavable ester bonds and a folic acid ligand for specific tumor targeting while remaining soluble in aqueous solutions without detectable aggregation at therapeutic dose. This CPT‐RNA nanoparticle exhibits efficient and specific cell binding and internalization, leading to cell apoptosis. Tumor growth is effectively inhibited by CPT‐RNA nanoparticles; the targeted delivery, strengthened by tumor ligand, further enhances tumor suppression. Compared with the traditional formulation, solubilization of CPT in aqueous buffer using RNA nanoparticles as a carrier is found to be safe and efficacious, demonstrating that RNA nanoparticles are a promising platform for the solubilization and the delivery of hydrophobic antitumor drugs.