Targeting and structural engineering of light-responsive nanoprobes for hierarchical therapy: construction, optimization, and applications in cancer stem cells.

Cancer stem cells (CSCs) possess the ability to self-renew and exhibit high differentiation potential, and they have been proven to be responsible for the maintenance, growth, and metastasis of tumors. As such, accurate identification and targeted therapy for CSCs are of great importance in clinical treatment. Here, a dual-targeted and light-responsive nanoprobe is presented, utilizing the reconstructed mesoporous SiO2 of a binary fatty acid eutectic mixture and a gold porous shell. The gold shell in the nanoprobe sustains a large absorption cross-section, providing a robust photothermal treatment effect against CSCs upon NIR irradiation. The photothermal effect simultaneously melts the eutectic mixture, which acted as the gating material, triggering the release of nuclear-targeted photosensitizers for photodynamic therapy (PDT). Additionally, to improve the hypoxic environment during PDT, hemoglobin (Hb) is conjugated to the nanoprobe using disulfide as a cross-linker, which can consume cellular glutathione while releasing Hb to deliver oxygen for PDT. Under the synergistic effect of photothermal therapy (PTT) and PDT, cytoplasmic organelles and intranuclear genetic materials are hierarchically damaged, initiating a cascade of reactions, including evident endoplasmic reticulum stress and inflammation. These responses, in turn, promote stem cell death and inhibit tumorigenicity. Furthermore, machine learning models, including random forest (FR), CatBoost, XGBoost, and LightGBM, were employed to optimize the reaction conditions for maximizing the synergistic effect, with CatBoost achieving the best performance. Additionally, antibody-conjugated nanoprobes effectively targeted colon cancer stem cells, demonstrating enhanced phototoxicity and the potential to suppress tumorsphere formation. Therefore, this dual-targeting nanoprobe demonstrates outstanding therapeutic integration performance and shows promise as a platform for synergistic PTT/PDT therapy of CSCs.