In this work, we show a new therapeutic approach using 40–120 keV X rays to deliver a radiation dose at the isocenter located many centimeters below the skin surface several hundred times greater than at the skin and how this dose enhancement can be augmented with nanomaterials to create several thousand-fold total dose enhancement effect. This novel approach employs a needle X-ray beam directed at the isocenter centimeters deep in the body while continuously scanning the beam to cover a large solid angle without overlapping at the skin. A Monte Carlo method was developed to simulate an X-ray dose delivered to the isocenter filled with X-ray absorbing and catalytic nanoparticles in a water phantom. An experimental apparatus consisting of a moving plastic phantom irradiated with a stationary 1 mm needle X-ray beam was built to test the theoretical predictions. X-ray films were used to characterize the dose profiles of the scanning X-ray apparatus. Through this work, it was determined that the X-ray dose delivered to the isocenter in a treatment voxel (t-voxel) underneath a 5 cm deep high-density polyethylene (HDPE) phantom was 295 ± 48 times greater than the surface dose. This measured value was in good agreement with the theoretical predicted value of 339-fold. Adding X-ray-absorbing nanoparticles, catalytic nanoparticles or both into the t-voxel can further augment the dose enhancement. For example, we predicted that adding 1 weight percentage (wp) of gold into water could increase the effective dose delivered to the target by onefold. Dose enhancement using 1 mm X-ray beam could reach about 1,600-fold in the t-voxel when 7.5 wp of 88 nm diameter silica-covered gold nanoparticles were added, which we showed in a previously published study can create a dose enhancement of 5.5 ± 0.46-fold without scanning focusing enhancement. Based on the experimental data from that study, mixing 0.02 wp 2.5 nm diameter small tetrakis hydroxymethyl phosphonium chloride (THPC)-coated gold nanoparticles, which created chemical enhancement, with the 7.5 wp 88 nm diameter silica-covered gold nanoparticles, could further double the dose effect at the isocenter, resulting in a total dose enhancement effect of 3,245 ± 600-fold. These results indicate that the three-dimensional scanning focusing method using a needle beam of X rays can deliver a dose several hundred times greater at a deeply embeded target located well below the skin surface. Total dose effect can be enhanced to several thousand-fold by augmenting the scanning focusing effect with X-ray-absorbing and catalytic nanoparticles in the t-voxel.