The use of ultrasmall gold nanoparticles (AuNPs) as drug delivery systems (DDSs) represents certain challenges, including limited targeting efficiency, uncontrolled drug release, and off-target drug toxicity. Herein, we synthesize a series of second near-infrared (NIR-II) region emitting AuNPs by incorporating both c(RGDfC) peptide and cucurbit[7]uril (CB[7]) for active and bio-orthogonal tumor-targeting, respectively. The CB[7]/c(RGDfC)-AuNPs exhibited rapid tumor accumulation and prolonged retention, which were utilized as nanocarriers to load oxaliplatin (OX) to afford OX@CB[7]/c(RGDfC)-AuNPs for targeted drug delivery and tumor chemotherapy. The mice treated with OX@CB[7]/c(RGDfC)-AuNPs achieved superior therapeutic outcomes compared to three times the dose of OX treatment (H-OX group). Meanwhile, the AuNPs showed excellent biosafety as opposed to obvious hepatotoxicity and severe hepatorenal toxicity observed in the mice treated with low dose of OX and H-OX, respectively. This renal-clearable DDS holds promise for precise drug delivery and controlled release, offering new perspectives and methods for clinical cancer treatment.