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Triple-negative breast cancer (TNBC) is recognized as the most malicious form of breast cancer and exhibits an alarming tendency for recurrence, a heightened propensity for metastasis, and an overwhelmingly grim prognosis. Therefore, effective therapy approaches for TNBC are urgently required. In this study, the interferon-stimulated gene 15 (ISG15) expression level was analyzed by bioinformatics and verified by Western blot analysis. The effects of ISG15 on the proliferation and metastasis of TNBC cells were assessed using MTT, Colony formation, EdU, Transwell, and Flow cytometry assays. We also developed a cancer cell-biomimetic nanoparticle delivery system and evaluated its therapeutic efficacy in vivo. In this study, we reported that ISG15 was upregulated in TNBC, and its high expression level correlated with an increased risk of tumorigenesis. Through in vitro and in vivo studies, we discovered that ISG15 knockdown drastically suppressed cell proliferation, invasion, and migration and induced apoptosis in TNBC cells. Our findings revealed that ISG15 was a candidate therapeutic target in TNBC because of its key role in malignant growth and invasion. Moreover, co-immunoprecipitation showed that ISG15 exerted oncogenic functions through its interaction with ATP binding cassette subfamily E member 1 and activated the Janus kinase/signal transducers and activators of the transcription signaling pathway. Furthermore, we created a nanoparticle-based siRNA camouflaged using a cancer cell membrane vesicle delivery system (the CM@NP complex) and confirmed its therapeutic effects in vivo. Our findings confirmed that ISG15 may play a pivotal oncogenic role in the development of TNBC and that CM@siRNA-NP complexes are an effective delivery system and a novel biological strategy for treating TNBC. • ISG15 upregulation occurs in TNBC, while its high expression level correlates with increased risks of tumorigenesis. • Knockdown of ISG15 dramatically suppressed cell proliferation, invasion, and migration and induced apoptosis in TNBC cells. • ISG15 acted as a candidate therapeutic target in TNBC for its key role in the invasive and metastatic growth we have identified. • We created a nanoparticle-based siRNA camouflaged by a cancer cell membrane vesicle delivery system (CM@NP complexes) and examined its therapeutic effects in vivo. • Co-IP identified that ISG15 exerted oncogenic functions through its interaction with ABCE1 and activated JAK/STAT signaling pathway. • ISG15 may play a pivotal oncogenic role in the development of TNBC, and the CM@NP complexes are an effective delivery system and a novel biological strategy for treating TNBC. [ABSTRACT FROM AUTHOR]