Designed Fabrication Of Gold-based Heterogeneous Phototherapeutic Nanoagents For Tumor Phototherapy

As a non-invasive therapeutic modality with spatio-temporal controllability and biocompatibility,phototherapy has attracted enormous attention in anti-tumor treatments.Photodynamic therapy（PDT）and photothermal therapy（PTT）are two conventional light-mediated therapies.Under light irradiation,PDT employs reactive oxygen species（ROS）generated from O₂ by photosensitizers to kill tumor cells,however,the oxygen-dependency of PDT leads to the result that its efficacy can be significantly affected by tumor hypoxia.PTT utilizes local heat generated by photothermal agents to ablate tumors,nevertheless,compared to other light-mediated therapies,the anti-tumor efficacy of PTT can be significantly compromised by light attenuation in tissues.In recent years,the newly developed photocatalytic therapy（PCT）,which catalyzes the reduction/oxidation reactions of substrates via the electrons/holes generated from photocatalysts driven by solar energy,can generate toxic ROS or to affect the biological reaction process in vivo for further tumor killing,is superior in overcoming the challenges faced by the PTT and PDT.Therefore,the rational design and fabracation of high-performance photocatalysts and the in-depth investigation of their anti-tumor performances under low-power laser irradiation is one of the“hot pots”in anti-tumor phototherapy.The development of photocatalysts that can effectively harvest near infrared（NIR）light and possess enzyme-mimic catalytic activities is pivotal in tumor phototherapy.The designed integration of plasmonic metal/semiconductor nanostructures is anticipated to achieve an enzyme-mimic photon-driven sub-nanostructural transformation,so as to facilitate the catalytic activity regulation of nanozymes in harsh biological microenvironments for highly efficient PCT.In this thesis,a sub-nanostructural transformable gold@ceria（STGC）nanocatalyst was synthesized by controlled assembly of ultrafine ceria nanoparticles（Ce O₂ NPs）onto the plasmonic gold nanorods（GNRs）.Once triggered by 808 nm low-power NIR(50 m W cm^-2),plasmon-excited hot electrons in Au core directly transferred from Au to Ce O₂,converting Ce⁴⁺to Ce³⁺and inducing the generation of active oxygen vacancies（OVs）to dynamically reconstruct the sub-nanostructure of STGC-PEG.The sub-nanostructural transformation of STGC enhances its peroxidase（POD）-like activity and unprecedentedly activates plasmon-promoted oxidase（OXD）-like activity,possessing remarkable photocatalytic performance.In the process of phototherapy,high light fluency can inevitably induce the necrosis of the normal tissues,thus it is appealing to achieve potent phototherapy with minimal light intensity,especially for deep-seated tumors requiring light penetration through tissue barriers that diminish light intensity at the tumor sites.Hence,low power NIR-driven PCT is urgently needed in anti-tumor treatment.Benefiting from the remarkable photocatalytic performance of STGC,STGC can generate abundant ROS both in cellular level and in vivo anti-tumor experiments,enabling highly efficient low power NIR-driven PCT.In addition to the direct killing of tumor cells,in recent decades,phototherapy has also been widely reported to induce immunogenic cell death（ICD）that in turn triggers systematic immunological response to combat tumor metastasis.In this thesis,we further report on the designed fabrication of anisotropic gold/end-ceria nanorods（GCNRs）by selectively depositing semiconducting ceria nanosheets onto the two ends of GNRs.Site-selective deposition of semiconductors onto the two ends of plasmonic metals enables an effective harvest of the NIR light,and allows the hot charge carriers（electron-hole pairs）generated to be freely accessed by the reactants,resulting in a superior photocatalytic activity via improving the electron-hole separation and hot charge carriers utilization.Upon 808 nm low-power NIR(300 m W cm^-2)light irradiation,GCNRs generated electron-hole pairs,whereafter an efficient electron-hole spatial separation along the longitudinal axis of GCNRs occurs due to the end-deposition morphology.Here,the hot electrons can transfer from Au to Ce O₂,dramatically enhancing the POD-and OXD-like activities of GCNRs through Ce⁴⁺-Ce³⁺shift and OVs generation to promote ROS generation.The generated ROS can induce ICD that in turn triggers systematic immunological response;in the meantime,the plasmon-generated hot holes left in GNRs can drive the oxygen-evolution half-reaction（OER）,alleviating tumor hypoxia to promote the repolarization of tumor infiltrated M2-type tumor-associated macrophages（TAMs）toward the antitumoral M1-type.Thus,the above-mentioned effects of hot electronics/holes in GCNRs can concurrently modulate the immunosuppressive tumor microenvironment（TME）via ICD induction and hypoxia relief,enabling highly efficient tumor photoimmunotherapy to inhibit the growth of primary and distant tumors,and the metastasis of tumor cells.In this thesis,a series of GNRs-based heterogeneous photocatalysts with enzyme-mimic activities were developed by chemical,physical,and pharmaceutical methods,and via structure optimization and surface ligand modification:（1）A sub-nanostructural transformable gold@ceria nanozyme was synthesized,which could realize enzyme-mimic photon-driven structural transformation-mediated catalytic activities regulation for low power NIR light-driven tumor PCT.（2）An anisotropic gold/end-ceria nanorod was fabricated,which can achieve an efficient electron-hole spatial separation with an improved hot charge carriers utilization in photocatalysis due to the end-deposition morphology.The generated hot electrons/hot holes could modulate the immunosuppressive TME via concurrent ROS-mediated ICD-induction and hypoxia relief for highly efficient photoimmunotherapy.The studies in the thesis provide a platform for the development of novel therapeutic agents in tumor phototherapy,and pave the way for in-depth investigation of photocatalysts in biomedical applications.