Currently, it is still a challenge to develop an organic photosensitizer (PS) with outstanding near-infrared absorption, low O2 dependence, precise tumor targeting and rapid clearance through the kidney to improve the overall outcome of phototherapy. In this study, we have designed an organic PS (NcPB) with an excellent near-infrared light absorption through a refined molecular strategy. Meanwhile, NcPB was assembled into nanoparticles with different sizes (NanoNcPB-1 and NanoNcPB-0) by a supramolecular modulation strategy. As the results, the nanoparticle with an ultra-small size (NanoNcPB-1) generated a large number of superoxide anion (O2•−) in a low-O2-dependent manner and release plenty of heat. Furthermore, the results of in vivo experiments demonstrated that NanoNcPB-1 actively accumulated in tumor tissues and showed a 92% tumor inhibition after photodynamic and photothermal combination therapy. More importantly, NanoNcPB-1 could be rapidly cleared from the body of mice via the renal pathway, which alleviates potential side effects of prolonged retention of PS in the circulation.