Construction Of Endogenous Stimuli-responsive Persistent Luminescence Nanoprobes For Imaging And Bacterial Killing

Persistent luminescence nanoparticles（PLNPs）can continue to emit light after the excitation stops,which can effectively avoid autofluorescence interference in biological tissues and greatly improve the signal-to-noise ratio.Especially,near-infrared luminescent PLNPs have shown important application prospects in the field of biomedical imaging due to their strong tissue penetration ability,ultra-long afterglow,and re-activation by red LED lights.Bacterial infectious disease is one of the major diseases that cause human death,and poses a serious threat to human health.At present,the most effective method for clinical treatment of bacterial infection is antibiotic therapy.With the unreasonable use of antibiotics,bacterial resistance is becoming increasingly severe,and bacterial infection treatment has once again fallen into a dilemma.Therefore,there is an urgent need to improve existing treatment methods and find new strategies to combat bacterial infection.There are usually a few problems in the design of bactericidal materials,such as lack of targeting,poor specificity,premature drug release and low biological safety.Nanoprobes with both imaging and therapeutic functions can provide imaging and specific treatment of lesion site,improving treatment efficiency while minimizing potential side effects.Therefore,nanomedicines that integrating diagnosis and treatment have received widespread attention in the field of biomedicine.This dissertation aims to develop persistent luminescence nanomaterials based endogenous activated theranostic nanoprobes,and explore their application in imaging-guided bactericidal therapy.The main research findings are as follows:The low utilization of antibiotics and the inability to achieve real-time monitoring of pathological status and treatment processes often lead to poor treatment performance for bacterial infection.To overcome these problems,a nanoprobe（PZC-FA）for targeted imaging of bacterial infection site and acid responsive antibiotic therapy was developed.Reactivatable near-infrared persistent luminescence nanoparticles(Zn_1.25Ga_1.5Ge_0.25O₄:0.5%Cr³⁺,2.5%Yb³⁺,0.25%Er³⁺)was used as the core for autofluorescence interference-free bioimaging,while zeolitic imidazolate framework-8（ZIF-8）was coated on its surface through a mild one-pot method as a carrier for antibiotic cefazolin.Further modifying folic acid（FA）endowed the nanoprobe with targeting ability.The prepared PZC-FA was intravenously injected into the mice infected with Staphylococcus aureus,and targeted and aggregated to the infection site due to the overexpression of folate receptors by bacteria at the infection site,achieving afterglow imaging of the bacterial infection site.At the same time,the ZIF-8 shell of PZC-FA degraded and released cefazolin for chemotherapy under weakly acidic conditions of the bacterial infection site.This treatment system can achieve precise release of loaded drugs and effective monitoring of the treatment process,providing a design idea for the construction of an integrated imaging and treatment platform.In order to expand the application of antibiotic-free antibacterial strategies in the treatment of bacterial infection,a multifunctional persistent luminescence theranostic nanoprobe was constructed for the chemodynamic therapy（CDT）of bacterial infection.The multifunctional theranostic nanoprobe（PMG）was designed with PLNPs as the core,and p H-responsive manganese-based metal-organic framework（Mn-MOF）as the shell for loading glucose oxidase（GOx）.The platform was used for"turn-on"afterglow imaging and combined cascade chemodynamic therapy of bacterial infection.The afterglow of PLNPs was quenched by the coating of Mn-MOF in the platform,but recovered when the platform was at the acid bacterial infection site due to the collapse of Mn-MOF,so that the lesion site was imaged.In addition,GOx consumed glucose to inhibit bacterial metabolism,and produced gluconic acid and H₂O₂ through enzymatic reactions.Mn²⁺triggered a Fenton-like reaction to produce hydroxyl radicals（·OH）to kill bacteria by inducing lipid peroxidation in bacterial cells.The utilization of non-toxic glucose as"fuel"and the cascade catalysis for the formation of highly cytotoxic·OH in this process demonstrated an efficient and biosafe antimicrobial strategy without antibiotic involvement.The microenvironment of the infection site often has unusually high levels of glutathione（GSH）,which can clear reactive oxygen species（ROS）,severely impinging the effects of chemodynamic therapy.Achieving efficient Fenton reaction and intracellular GSH consumption is critical for improving CDT efficiency.Therefore,a simple,efficient infection microenvironment GSH-activatable nanoprobe(PLNPs-CS-Cu²⁺)was further developed.PLNPs was used as the core,while chitosan（CS）was used as the linker to fix copper ions on the surface of PLNPs.Cu²⁺served as a switch of afterglow signal.The afterglow of PLNPs was quenched by Cu²⁺under normal physiological conditions,but restored due to the conversion of Cu²⁺into Cu⁺by the high concentration of GSH at the infection site,achieving autofluorescence interference-free bioimaging.In addition,Cu²⁺consumed GSH of the infection site through redox reaction,and the generated Cu⁺provided CDT function,consumption of GSH further amplifies intracellular oxidative stress and enhances the efficacy of chemodynamic therapy.This work provides useful insights for the development of an integrated diagnostic and therapeutic nanoprobe for clinical treatment of bacterial infection.