Renal clearance is critical for nanodrug to avoid the long‐term body retention‐related side effects, while it is difficult to achieve efficient tumor accumulation and retention. The over‐developed lysosomes in cancer cells have become an emerging target for more precise and effective cancer therapy. Herein, a pH‐responsive reversible self‐assembled Cu_2‐xSe‐BSA, which can be renal cleared under neutral or basic conditions, is developed for selectively targeted aggregation in cancer lysosomes with enhanced tumor accumulation and retention. Moreover, the aggregation of Cu_2‐xSe‐BSA can enhance the photoacoustic imaging signal, photothermal therapy, and chemodynamic therapy capability. Cu_2‐xSe‐BSA accumulated in lysosomes cannot only induce lysosomes swelling, but also generate reactive oxygen species in situ, causing lysosomal membrane permeabilization and finally lysosomal cell death. Notably, the assembled Cu_2‐xSe‐BSA can dissociate to be renal clearable after the treatments are completed and left the acid tumor microenvironment, being of great significance both in scientific research and clinical trial.