The Design,Systhesis Of Smart Responsive Nanomaterials Based On Bismuth/Manganese And Their Application In Triple-Negative Breast Cancer Therapy

Triple-negative breast cancer（TNBC）is a subtype of breast cancer with the characteristics of difficult diagnosis,strong invasiveness,and low cure which is still lack of effective treatments due to no specific receptors and complex tumor microenvironment（TME）.In recent years,the development of nanotechnology has inovated novel ideas for improving the efficacy of TNBC.Thus,a variety of TME-responsive nanomaterials have been created to modify or utilize TME for tumor therapy.However,most of materials with single responsive-modality are not enough to kill tumors.To solve these problems,we adopted a dual research perspective:from the perspective of TME and physical/chemical properties of materials,constructing a series of smart multi-modal responsive nanomaterials to achieve the therapeutic effect of"1+1>2".In this work,we selected manganese with multivalent property and bismuth with photothermal effect and CT capability as the core of the system to establish two smart responsive nanomaterials for the diagnosis and treatment of TNBC,obtaining the following results:1)A kind of bismuth-manganese-based nanoparticles with honeycomb structure,Bi₂O₃/MnO_x-NH₂/ICG（BMNI）,was designed,and the formation mechanism of its honeycomb structure proposed,enabling a large amount of ICG load（50.6 w%）.Subsequently,biomimetic nanoparticles with targeted ability were obtained,Bi₂O₃/MnO_x-NH₂/ICG@CM（m BMNI）.The nanoparticles can trigger photothermal therapy（PTT）and photodynamic therapy（PDT）under an exogenous NIR stimulation,and the multivalent manganese respond to the endogenous GSH/H₂O₂stimulation,which leads to the consumption of GSH and induces the production of O₂ and·OH,triggering chemodynamic therapy（CDT）.In addition,the consumption of GSH and the production of O₂ can promote PDT,while the high temperature of PTT enhances CDT.Cell and animal experiments proved that m BMNI has good mutual reinforcement of internal and external response for TNBC therapy.Our strategy for honeycomb-like structure and mechanisms of mutual reinforce between internal and external responses will extension the excellent nanoplatforms for tumor therapy in the future.2)A type of bismuth-manganese-based nanoflower,BDS-GOx@MnO_x,with smart responses to TME was fabricated.Under acidic microenvironment of TNBC,the MnO_x shell was degraded gradually to release glucose oxidase（GOx）,which can seize the glucose needed by the tumor to trigger starvation treatment（ST）accompanying with H₂O₂ production.Meanwhile,high-valent manganese reacts intelligently with GSH and was reduces to Mn²⁺to induce CDT.In addition,the nanoflower with multi-modal response and enhanced CT capacity were also confirmed in cells and animals.Therefore,the integrated diagnosis and treatment nanoflower has a good application prospect.