Abstract
<jats:p>Triple-negative breast cancer (TNBC) lacks clinically actionable receptors, limiting targeted therapy and increasing reliance on systemic chemotherapy, which often causes off-target toxicity and chemoresistance. Here, we present a computational strategy employing a newly developed water-soluble near-infrared (NIR) cyanine probe (Cy-Cl) as a multi-receptor targeting platform for TNBC. Unlike previous approaches focused on single biomarkers, CyCl simultaneously targeted ICAM-1, EGFR, CD44, and NRCAM, exhibiting the strongest affinity toward the more tumour-selective receptors NRCAM and CD44, thereby potentially reducing off-target interactions. Doxorubicin was identified as the optimal therapeutic cargo and, upon conjugation with Cy-Cl, further enhanced receptor binding across all targets. Molecular dynamics simulations confirmed stable receptor-ligand complexes under physiological conditions. Collectively, these findings establish Cy-Cl as a versatile NIR-based diagnostic and therapeutic scaffold for receptor-targeted drug delivery and NIR molecular imaging of TNBC, with NRCAM representing the most promising receptor for selective targeting.</jats:p>