A bioswitchable siRNA delivery system: RNAi therapy based on tetrahedral framework nucleic acids for bone defect repair.

Craniofacial bone defects, caused by trauma, congenital abnormalities, or various diseases, present a significant challenge in regenerative medicine. One approach to addressing this problem is the use of RNA interference (RNAi) technology with small interfering RNA (siRNA). CKIP-1 is a negative regulatory molecule for bone formation. However, direct applications of CKIP-1 siRNA for bone defects are still limited. The instability and poor cellular uptake ability of CKIP-1 siRNA restrict its clinical applications. A new drug delivery system is critically needed to enhance the effectiveness and potential applications of CKIP-1 siRNA. Tetrahedral framework nucleic acid (tFNA) is a promising drug delivery system due to its stability and transport abilities. In this study, we developed a bioswitchable siRNA delivery system (BiRDS) based on tFNA to carry CKIP-1 siRNA and examined its effect on bone defect repair. siRNA was successfully loaded into the tFNA core, forming BiRDS, which improved siRNA stability and cellular uptake. After entering cells, BiRDS exposed siRNA, enhancing CKIP-1 silencing efficiency. This system significantly promoted osteogenic differentiation and bone regeneration in rat mandibular bone defects, offering a new strategy for bone regeneration therapy.