Tumor Microenvironment-Responsive Nanoherb Delivery System for Synergistically Inhibition of Cancer Stem Cells

Multidrug resistance in cancer stem cells (CSCs) is a major barrier to chemotherapy; hence, developing CSC-specific targeted nanocarriers for efficient drug delivery is critical. In this study, monodisperse hollow-structured MnO₂ (H-MnO₂) with a mesoporous shell was created for efficient targeted drug delivery. An effective therapeutic compound isoliquiritigenin (ISL) was confirmed to inhibit the lung cancer stem-cell phenotype by natural compound screening based on integrated microfluidic devices. The resultant H-MnO₂ showed a high drug-loading content of the potent CSC-targeting compound ISL and near-infrared fluorescent dye indocyanine green (ICG). In addition, H-MnO₂ was successively modified with hyaluronic acid (HA) to enhance targeting CSCs with high CD44 expression levels. The H-MnO₂@(ICG + ISL)@HA nanocomposites displayed promising chemotherapeutic and photothermal treatment capabilities, as well as NIR-triggered drug release, which showed excellent CSC-killing effects and tumor inhibition efficacy. Meanwhile, the development of the tumor was effectively restrained by NIR-triggered phototherapy and prominent chemotherapy without obvious side effects after tail vein injection of the nanocomposites in vivo. In summary, the prepared nanocomposites accomplished synergistic cancer therapy that targets CSCs, offering a versatile platform for lung cancer diagnosis and treatment.