ABSTRACT Triple‐negative breast cancer (TNBC) remains one of the most challenging breast cancer subtypes to treat due to the lack of well‐defined molecular targets. 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‐binding nanobodies (aCD13Nb) and tumor necrosis factor‐related apoptosis‐inducing ligand (TRAIL) via the SpyCatcher/SpyTag protein ligation system. This dual‐ligand nanoparticle exhibited enhanced and specific binding to CD13‐overexpressing TNBC cell lines, including HCC1937, MDA‐MB‐468, and BT‐549 cells. aCD13Nb‐mediated 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‐overexpressing 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‐ligand protein cage nanoparticles as an effective platform for targeted cancer therapy.
Jun et al. (Sun,) studied this question.