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D3 nanobody is a single-domain antibody fragment engineered to selectively bind with high affinity (KD = 2.2 nM) to mesothelin, an antigen overexpressed in pancreatic adenocarcinoma and other malignancies[1]. The nanobody comprises 125 amino acids (approx. 15 kDa) and is characterized by its strong interactions—hydrogen bonds and hydrophobic contacts—with mesothelin, resulting in stable and potent antigen binding[1]. Its therapeutic action includes inhibition of key tumor-promoting pathways (AKT/NF-κB) and downregulation of oncogenic EMT-related genes such as fibronectin 1 and twist1. Preclinical studies have demonstrated that D3 nanobody alone significantly inhibits tumor progression and, when conjugated to gemcitabine-loaded liposomes (D3-LNP-GEM), enhances delivery, antitumor efficacy, and reduces off-target toxicity, specifically targeting mesothelin-positive tumors in in vivo pancreatic cancer models[1]. Developed as a targeted therapy for mesothelin-expressing cancers, D3 nanobody exploits its small size and superior tissue penetration relative to conventional antibodies, aiming for high intratumoral accumulation and minimal systemic exposure[1].
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