Engineered modifications of nanomaterials inspired by nature hold great promise for disease-specific imaging and therapies. However, conventional polyethylene glycol modification is limited by immune system rejection. The manipulation of gold nanorods (Au NRs) modified by endogenous proteins (eP@Au) is reported as an engineered biomodulator for enhanced breast tumor therapy. The results show that eP@Au NRs neither activate inflammatory factors in vitro nor elicit rejection of immune responses in vivo. Tumor-specific eP@Au NRs exhibit a dual-modal imaging capability and trigger a mild photothermal effect under near-infrared light irradiation, enabling highly efficient imaging and therapy of tumors. Transcriptome sequencing and confirmatory experiments reveal that the antitumor effect is mainly attributed to the repression of PI3K-Akt/MAPK signaling pathways at the molecular level. This powerful and surprising in situ eP-regulated biomodulation demonstrates the advantages of convenient fabrication, inert immunogenicity, and biocompatibility, providing an alternative strategy for biomedical imaging and therapy.