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Cluster of differentiation 13 (CD13), a cell surface aminopeptidase, is highly expressed in various tumors and play critical roles in promoting angiogenesis, aberrant proliferation, invasion, and metastasis. In this study, we investigated CD13 as a potential therapeutic target in TNBC cell lines to enable targeted therapy. Accordingly, we employed a protein cage nanoparticle, AaLS\/TRAIL\/aCD13Nb, which simultaneously displays CD13\u2010binding nanobodies (aCD13Nb) and tumor necrosis factor\u2010related apoptosis\u2010inducing ligand (TRAIL) via the SpyCatcher\/SpyTag protein ligation system. This dual\u2010ligand nanoparticle exhibited enhanced and specific binding to CD13\u2010overexpressing TNBC cell lines, including HCC1937, MDA\u2010MB\u2010468, and BT\u2010549 cells. aCD13Nb\u2010mediated tight binding facilitated sustained interaction of TRAIL with death receptors, resulting in robust activation of apoptotic signaling cascades and significantly enhanced therapeutic efficacy in CD13\u2010overexpressing TNBC cell lines. Moreover, systemic administration of AaLS\/TRAIL\/aCD13Nb via intravenous injection markedly suppressed tumor growth in an HCC1937 xenograft mouse model, without evidence of systemic toxicity. These findings validate CD13 as a promising therapeutic target in TNBC and underscore the potential of dual\u2010ligand protein cage nanoparticles as an effective platform for targeted cancer therapy.<\/jats:p>","DOI":"10.1002\/mabi.202500645","type":"journal-article","created":{"date-parts":[[2026,2,8]],"date-time":"2026-02-08T19:25:22Z","timestamp":1770578722000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Targeted Therapy for CD13\u2010Overexpressing Triple\u2010Negative Breast Cancers Using Apoptosis\u2010Inducing Protein Cage Nanoparticles"],"prefix":"10.1002","volume":"26","author":[{"given":"Heejin","family":"Jun","sequence":"first","affiliation":[{"name":"Department of Biological Sciences Ulsan National Institute of Science and Technology (UNIST)  Ulsan Republic of 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