Furin Enzyme-Responsive siRNA Delivery System for Efficient Anti-Hypoxia-Assisted Cancer Photodynamic Therapy

RNA interfering therapy has emerged as a promising therapeutic modality to treat cancer. The specific and efficient delivery of RNA into a tumor is crucial for achieving effective cancer gene therapy but remains a huge challenge. Herein, we report a novel furin-responsive small interfering RNA (siRNA) delivery vehicle with multiple functions for colorectal tumor treatment. A peptide-based siRNA delivery vehicle RVRR-P18-Gd, consisting of furin enzyme-specific peptide substrate Arg-Val-Arg-Arg (RVRR) with positive charge for siRNA binding, a Gd(III) chelated 1,4,7,10-tetraazacyclododecane-N,N ',N '',N '''-tetraacetic acid (DOTA) (DOTA-Gd) for magnetic resonance imaging, and purpurin 18 as photosensitizer for photodynamic therapy (PDT), was rationally designed and synthesized. Taking advantage of the cationic amphiphilic feature, RVRR-P18-Gd molecules spontaneously self-assembled with negatively charged Hif-1 alpha siRNA into stable nanoparticles via attractive electrostatic interaction, which effectively prevented siRNA degradation by nucleases, prolonged the circulation half-life, and enhanced tumor accumulation. Moreover, the specific release of Hif-1 alpha siRNA mediated by endogenous furin significantly downregulated Hif-1 alpha expression in colorectal cancer cells, resulting in enhanced therapeutic susceptibility, and with the PDT effect, effectively suppressed HCT116 tumor growth in living mice. This work highlights a powerful and universal approach to precisely deliver siRNA to targeted tumors for efficient synergistic therapy. [GRAPHICS] .