Multifunctional Near-infrared Light Response Bismuth-based Nanomaterials For Accurate Tumor Theranostics

In recent years,near-infrared light-responsive theranostics have drawn attention owing to their simplicity,safety,non-invasiveness,high selectivity and targeting properties.Bismuth（Bi）-based nanoagents possess wide application prospects in the area of tumor theranostics owing to their excellent electrical,optical and thermodynamic properties.Based on this,we have designed and prepared four Bi-based near-infrared（NIR）light-responsive nanoplatform and analyzed their structural and functional properties.Besides,we investigated the imaging and synergistic anti-tumor therapeutic effects of these multi-functional nanoplatforms at the cellular and animal level,and discussed the internal mechanism of their theranostics effects,hoping to provide evidence and theoretical frames for subsequent development of tumor precise treatments.Firstly,we designed a smart theranostics nanoplatform based on a hyaluronic acid-doped polypyrrole-coated bismuth selenide loading with a zinc phthalocyanine nanodish complex（Bi₂Se₃@HA-doped PPy/Zn Pc）for multimodal imaging-guided combined anti-tumor phototherapy.Besides the good ability for infrared thermal,photoacoustic,fluorescence,and X-ray computed tomography imaging,the nanodish complex exhibited high photo-heat conversion efficiency for photothermal therapy（PTT）,as well as remarkable optical absorption of the coefficient for photodynamic therapy（PDT）under NIR irradiation.However,hyperthemia（>50°C）induced heating damage of nearby normal organs and inflammatory diseases are the main challenges for PTT of tumors.To overcome this limitation,Bi₂Se₃ hollow nanocubes（HNCs）,redox-responsive biomodal tumor-targeted nanoplatforms,were first fabricated.The Bi₂Se₃ HNCs were then modified with hyaluronicacid（HA）through redox-cleavable linkage（-s-s-）and loaded by gambogic acid（GA）,which was a type of heat-shock protein（HSP）inhibitor.Such HNC-s-s-HA/GA could achieve multi-spectral optoacoustic tomography/X-ray computed tomography imaging-guided low-temperature photothermal-radio combined therapy（PTT-RT）.In addition,although PTT can take advantages of local hyperthermia to ablate tumor cells,its effect on metastatic tumor cells is still limited.To overcome these obstacles,an imiquimod（R848）loaded and PEG-modified Bi₂Se₃ nanocage（NC）,which could efficiently destroy the tumors thus producing enough tumor-associated antigens（TAA）was reported in this study.What’s more,with the existence of R848,a toll-like receptor-7 agonist,this nanoplatform could generate strong anti-tumor immune responses to realize tomur immunotherapy.Moreover,immunogenic Bi₂Se₃NC-PEG/R848 mediated PTT sensitized tumors to checkpoint inhibition mediated by a PD-L1 antibody,which could not only ablate tumor cells upon NIR laser,but also cause strong anti-tumor immunity to suppress distant tumor growth post-PTT.Moreover,due to the highly complex biological formation procedure,tumor is always associated with proliferation,migration and inflammation during treatment.Herein,a novel strategy of boosted photocatalytic activity induced nicotinamide phosphoribosyl transferase（NAMPT）-regulating therapy was used for tumor inhibition based on FK866 loaded bismuth-humic acids heterojunction（Bi-HA/FK866）.The reactive oxygen species（ROS）produced by Bi-HA/FK866 with the existence of NIR could induce DNA damage of the tumor cells,thus enhancing the sensitivity to the inhibitor of NAMPT（FK866）to downregulate nicotinamide adenine dinucleotide/extracellular regulated protein kinases/nuclear factor kappa-B（NAD/ERK/NF-κB）signal pathways,and eventually simultaneously preventing tumor progression.Moreover,the decreased NAD could reduce the expression of nicotinamide adenine dinucleotide phosphate（NADPH）and further suppress the innate antioxidant defense system by downregulating oxidized glutathione（GSSG）.