PD-L1 Aptamer–Functionalized Mesoporous Silica Nanoparticles for Targeted Doxorubicin Delivery in Triple-Negative Breast Cancer

Juntao Tan,1,* Zixi Hu,2,* Da Huang,1,* Lu Chen,1 Liangliang Min,1 Qi-Hua Jiang,3 Zhihua Li1,31Jiangxi Province Key Laboratory of Breast Diseases, Nanchang People’s Hospital/The Affiliated Nanchang People’s Hospital of Nanchang Medical College, Nanchang, Jiangxi, People’s Republic of China; 2Clinical Laboratory Center, The First Affiliated Hospital of Guilin Medical University, Guilin, Guangxi Zhuang Autonomous Region, People’s Republic of China; 3Department of Breast Surgery, Nanchang People’s Hospital/The Affiliated Nanchang People’s Hospital of Nanchang Medical College, Nanchang, Jiangxi, People’s Republic of China*These authors contributed equally to this workCorrespondence: Zhihua Li, Jiangxi Province Key Laboratory of Breast Diseases, Nanchang People’s Hospital/The Affiliated Nanchang People’s Hospital of Nanchang Medical College, No. 2, Xiangshan South Road, Xihu District, Nanchang, Jiangxi, 330008, People’s Republic of China, Tel +8679186617472, Fax +8679186617472, Email [email protected] Qi-Hua Jiang, Department of Breast Surgery, Nanchang People’s Hospital/The Affiliated Nanchang People’s Hospital of Nanchang Medical College, No. 2, Xiangshan South Road, Xihu District, Nanchang, Jiangxi, 330008, People’s Republic of China, Tel +8679186617472, Fax +8679186617472, Email [email protected]: Triple-negative breast cancer (TNBC) remains highly aggressive and lacks effective molecularly targeted therapies. Programmed death-ligand 1 (PD-L1) represents a potential cell-surface target for selective drug delivery.Objective: To develop and evaluate a PD-L1 aptamer–functionalized mesoporous silica nanoparticle system loaded with doxorubicin (Apt-PD-L1-MSN/DOX) for targeted DOX delivery in TNBC.Methods: Apt-PD-L1-MSN/DOX was synthesized and characterized by TEM, DLS, zeta-potential measurement, FT-IR, and UV–Vis analysis. DOX release was evaluated at pH 7.4, 6.5, and 5.0. Cellular targeting, cytotoxicity, and aptamer-blocking effects were assessed in MDA-MB-231 and MCF-10A cells. In vivo fluorescence distribution, antitumor efficacy, and short-term safety were evaluated in MDA-MB-231 xenograft-bearing mice.Results: Aptamer functionalization increased the hydrodynamic diameter from approximately 95 to 106 nm, with an estimated surface-associated aptamer loading of ~6.65 nmol/mg. DOX release was pH dependent, remaining below 40% at pH 7.4 but exceeding 80% at pH 5.0 after 96 h. Apt-PD-L1-MSN/DOX showed enhanced cellular targeting and the lowest IC50 in MDA-MB-231 cells (~0.8 μg/mL vs ~1.6 μg/mL for MSN/DOX and ~2.0 μg/mL for free DOX). Aptamer pre-blocking attenuated its cytotoxic effect. In vivo, Apt-PD-L1-MSN/DOX showed stronger tumor-associated fluorescence, greater tumor-growth inhibition, increased apoptosis, and prolonged survival, without overt short-term hepatic or renal toxicity.Conclusion: Apt-PD-L1-MSN/DOX shows promise as a PD-L1 aptamer-guided platform for targeted DOX delivery in the evaluated TNBC model.Keywords: PD-L1 aptamer, mesoporous silica nanoparticles, triple-negative breast cancer, targeted drug delivery, doxorubicin