Tetrahedral framework nucleic acids (tFNAs) have attracted extensive attention as drug nanocarriers because of their excellent cellular uptake. However, for oligonucleotide cargos, tFNA mainly acts as a static delivery platform generated via sticky-ended ligation. Here, inspired by the original stable space inside the tetrahedral scaffold, a dynamic lysosome-activated tFNA nanobox is fabricated for completely encapsulating a short interfering RNA (siRNA) of interest. The closed tetrahedral structure endows cargo siRNA with greater resistance against RNase and serum and enables solid integration with the vehicle during delivery. Moreover, the pH-responsive switch of nanobox allows the controlled release of siRNA upon entry into lysosomes at cell culture temperature. Based on protective loading and active unloading, an excellent silencing effect on the target tumor necrosis factor alpha (TNFα) gene is achieved in in vitro and in vivo experiments. Conclusively, the nanobox offers a dynamic pH-sensitive confinement delivery system for siRNA and can be an extendable strategy for other small RNA.