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

Abstract

Background 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.