Biodegradable Multifunctional Nanotheranostic Based On Ag₂S-doped Hollow BSA-SiO₂,Used For The Research Of Enhancing ROS-Feedback Synergistic Antitumor Therapy

Objective:Prepared self-feedback nanosystem Ag2S-GOx@BHS NYs to realize reactive oxygen species（ROS）induced multi-step therapy and near-infrared window fluorescence（NIR-II FL）and photoacoustic（PA）imaging guided precise photothermal therapy（PTT）.Methods:1.Synthesis of Ag2S@Hollow BSA-SiO2（Ag2S@BHS）Ag₂S@BHS were first prepared via a novel one-pot synthesis using BSA and CTAB as structure-directing agents.First,125 mg of BSA and 35 mg of CTAB were mixed with 4m L of water under stirring for 30 min.One milliliter of HNO₃（1 M）and 20 mg of Ag NO₃were quickly added.After reacting for 30 min,the p H was adjusted to 12 and maintained for12 h.TEOS（0.5 m L）was added dropwise under vigorous stirring for 24 h.The products were purified via centrifugation and then dispersed in NH₄NO₃ solution(15 mg m L^-1)to remove the template.Finally,brown powder was obtained by washing with water three times and then drying in a vacuum oven.2.Synthesis of Ag2S-GOx@Hollow BSA-SiO2（Ag2S-GOx@BHS）In a typical synthesis,5 mg of Ag₂S@BHS powder was dispersed in 5 m L of water,followed by adding 1 m L of GOx（1 mg m L-1）.Afterward,the solution was stirred vigorously for 12 h.The resulting Ag₂S-GOx@BHS was separated by centrifugation.3.CharacterizationThe BET isotherm of Ag₂S-GOx@BHS was characterized by a Micromeritics Tristar3000 system.Transmission electron microscopy（TEM）observations were conducted using JEOL-2100F.X-ray photoelectron spectroscopy（XPS,ESCA-LAB250）was used for analyzing the chemical valence of the sample.UV-vis absorption spectra were recorded on a UV-vis spectropho-tometer（Perkin Elmer）.NIR-II fluorescence emission spectra were performed on fluorescence microscopy with full-spectrum analysis（NIR-OPTICS）.The quantitative elemental analysis was detected by inductively coupled plasma-atomic emission spectroscopy（ICP-AES）（Plasma Quant MS）.Dynamic light scattering（DLS）was determined with Zetasizer Nano（Malvern Instruments Ltd.）.TG-DTA was measured by a thermogravimetric analyzer（Rigaku,TG8101D）.Results:Herein,a biodegradable hollow SiO₂-based nanosystem（Ag₂S-GOx@BHS NYs）is developed by a novel one-step dual-template（bovine serum albumin（BSA）and cetyltrimethylammonium bromide（CTAB））synthetic strategy for image-guided therapy.The Ag₂S-GOx@BHS NYs can be specifically activated in the tumor microenvironment via a self-feedback mechanism to achieve reactive oxygen species（ROS）-induced multistep therapy.In response to the inherent acidity and H₂O₂ at the tumor sites,Ag₂S-GOx@BHS would accelerate the structural degradation while releasing glucose oxidase（GOx）,which could efficiently deplete intratumoral glucose to copious amounts of gluconic acid and H₂O₂.More importantly,the sufficient H₂O₂ not only acts as a reactant to generate Ag⁺from Ag₂S for metal-ion therapy and improves the oxidative stress but also combines with gluconic acid results in the self-accelerating degradation process.Moreover,the released Ag₂S nanoparticles can help the Ag₂S-GOx@BHS NYs realize the second near-infrared window fluorescence（NIR-II FL）and photoacoustic（PA）imaging-guided precise photothermal therapy（PTT）.Conclusion:In summary,this work reports on the TME-activatable self-feedback mechanism for effective multistep therapy with excellent biodegradability and antitumor efficacy based on a novel hollow SiO₂-based nanosystem.The comprehensive study in vitro and in vivo demonstrated that the as-constructed Ag₂S-GOx@BHS NYs could be specifically activated in TME through a ROS-mediated feedback mechanism to continuously kill cancer cells,whereas it had no significant effect in normal cells.At tumor sites,Ag₂S-GOx@BHS would accelerate the structural degradation by inherent acidity and H₂O₂.With the release of GOx,the endogenous glucoses are specifically catalyzed into gluconic acid and H₂O₂.The high concentration of H₂O₂ induces oxidative stress and conversely attacks Ag₂S to release Ag⁺ions for ion therapy.Accordingly,the simultaneous generation of gluconic acid and H₂O₂ by the GOx-catalyzed oxidation reaction of glucose was accomplished to enhance the degradation behavior and reinforce the starving/oxidative/Ag-ion synergistic therapeutic effect.In addition,the efficient NIR-II FL and PA imaging of Ag₂S-GOx@BHS could guide precise photothermal therapy.Taken together,the development of a highly effective multistep therapy may provide a means to achieve curative responses in patients who cannot be cured by a single treatment approach alone.