2′-Fluorinated Antisense Oligonucleotide-Mediated Drug Self-Assembly Strategy for the Efficient Synergistic Anti-Tumor Therapy

Nanodrugs composed of pure pharmacologically active molecules have been extensively researched as emerging nanomedicines for cancer treatment. However, traditional preparation approaches are generally limited by low production rates, complicated preparation processes, and high production costs. Here, we presented a simple strategy for constructing drug-based nanoparticles (2′F-ASO/CPT NPs) consisting of pure therapeutic molecules by utilizing 2′-fluoro-substituted antisense oligonucleotide (2′F-ASO)-mediated self-assembly with the anticancer agent camptothecin (CPT). The 2′F-substitution could enhance the intermolecular interactions between DNA and CPT through electrostatic and dispersion interactions. The resulting 2′F-ASO/CPT NPs had a high drug loading capacity and improved drug stability. 2′F-ASO/CPT NPs could specifically respond to P-glycoprotein (P-gp) mRNA and inhibit the expression of P-gp, protecting CPT from P-gp-mediated drug efflux. Therefore, the synergistic anticancer effect caused by 2′F-ASO/CPT NPs could be successfully achieved. This work presented a new 2′F-ASO-mediated drug self-assembly strategy for carrier-free chemotherapy–gene therapy with the potential to enhance cancer treatment efficacy.