PD-L1-targeted multi-component nanosystem for synergistic triple-negative breast cancer therapy

An anti–programmed death-ligand 1 (PD-L1) antibody–functionalized, multi-component silica nanosystem (SNS) was constructed to integrate a nanosilver (Ag) core, doxorubicin (Dox), and a manganese dioxide (MnO 2 ) tumor-microenvironment–responsive shell, and its antitumor activity and mechanisms were evaluated in 4T1 triple-negative breast cancer (TNBC) models. SNS was synthesized and characterized by dynamic light scattering and transmission electron microscopy, and anti–PD-L1 was conjugated to the nanoparticle surface via EDC coupling. Without targeting-groups SNS (WTSNS) and single-component controls (Ag@SNS, Dox@SNS, and Mn@SNS) were prepared. In 4T1 cells, fluorescence microscopy assessed uptake and subcellular localization, CCK-8 evaluated in vitro cytotoxicity in 4T1 cells and L929 fibroblasts and generated IC50 values, comet assay examined DNA damage, and qPCR analyzed apoptosis-related transcripts. In 4T1 tumor-bearing mice, near-infrared imaging, tumor growth monitoring, histology, and body-weight recording assessed tumor accumulation, antitumor efficacy, and biosafety. SNS formed uniform spherical nanoparticles (~ 95 nm) with a zeta potential of ~ − 22 mV. PD-L1 targeting enhanced cellular internalization and tumor accumulation compared with WTSNS. CCK-8 assays showed concentration-dependent cytotoxicity, with IC50 values of 15.60 and 12.42 µg/mL for WTSNS and SNS in 4T1 cells and 22.52 and 22.04 µg/mL in L929 cells, respectively. SNS induced the strongest DNA damage, upregulated BAX, Caspase-3, Caspase-9, and downregulated BCL-2. In vivo, SNS achieved the greatest tumor growth suppression with stable body weight and no evident major-organ injury. Overall, anti–PD-L1-guided SNS supported synergistic TNBC therapy through DNA-damage-associated apoptosis.