Design And Biomedical Applications Of Near-infrared Responsive Nano-phototherapy Agents

Phototherapy is an innovative treatment method that uses specific light sources,particularly near-infrared（NIR）light,to activate photosensitizers to kill tumor cells or pathogenic microorganisms,achieving therapeutic effects.Phototherapy includes photodynamic therapy（PDT）and photothermal therapy（PTT）,and has attracted extensive attention in the field of disease diagnosis and treatment due to its minimally invasive nature,low toxicity,and spatiotemporal controllability.However,the field of phototherapy research still faces challenges such as insufficient photosensitizer performance,negative regulation effects of hypoxic microenvironments,and a lack of effective delivery strategies.In response,this thesis focuses on the rational design and delivery of photosensitizers,using functional inorganic nanomaterials as fundamental units to construct various light-controlled disease treatment systems.The research primarily focuses on optimizing the electron dynamics of photosensitizers,modulating the immune microenvironment of diseases,and enhancing photosensitizer delivery.The physicochemical properties and biological effects of photosensitizers are systematically explored.The specific content is as follows:To address the issue of rapid recombination of photogenerated carriers in inorganic phototherapeutic agents,this thesis proposes a strategy to modulate charge migration behavior through interface-induced electric field effects.By leveraging the Schottky barrier between cobalt oxide（Co₃O₄）and palladium nanocubes（Pd NCs）,a novel phototherapeutic agent,Co₃O₄@Pd,with an intrinsic electric field is successfully constructed.The reduced work function and increased surface potential of Co₃O₄@Pd promote the separation and migration of photogenerated electrons and holes,creating favorable conditions for the efficient generation of reactive oxygen species（ROS）.Under NIR light irradiation,the binding energy of Pd 3d in Co₃O₄@Pd decreases by 0.41 e V,confirming that the intrinsic electric field can direct electron migration from the semiconductor to the noble metal,providing longer-lived photogenerated carriers for the reaction system.Consequently,the hydroxyl radical signal peak intensity of Co₃O₄@Pd is enhanced by 253.9%compared to Co₃O₄.Additionally,the local surface plasmon resonance effect of the noble metal and the increased hole concentration improve the photothermal conversion efficiency of Co₃O₄@Pd to 40.50%.Cellular experiments and animal model evaluations demonstrate that under NIR light irradiation,Co₃O₄@Pd generates a significant amount of ROS,inducing apoptosis and immunogenic cell death（ICD）,achieving enhanced phototherapeutic anti-tumor effects with an in vivo tumor growth inhibition rate of up to 92.4%.To address the limitations of phototherapy due to the hypoxic and low-immunogenic characteristics of the tumor microenvironment（TME）,this thesis designs TME-responsive phototherapeutic agents using mesoporous silica as a template,which is fabricated by attaching manganese dioxide to an aminated surface（defined as NMMO）.Furthermore,a phototherapeutic adjuvant is constructed for reprogramming the immune-suppressing TME by loading immune-modulatory molecule,interleukin-21（IL-21）through an amide reaction,named NMMO@IL-21.NMMO exhibits excellent photothermal and photodynamic properties under NIR light irradiation.Its intrinsic enzyme-like catalytic activity can decompose H₂O₂ in the TME,generating O₂ and ROS,thereby alleviating tumor hypoxia and enhancing the efficacy of PDT.The enhanced light-responsive enzyme-like activity induces ICD in tumor cells,releasing tumor-associated antigens that activate anti-tumor immunity.IL-21 further activates T cells,promoting T cell infiltration in the spleen and tumor tissues of mice,overcoming T cell exhaustion in the TME and reshaping the immune-suppressive TME.The combination of the NMMO@IL-21 phototherapy system with the immune checkpoint inhibitorαPD-L1 significantly inhibited the growth of both primary and distal tumors.Approximately 86%of the mice survived 80 days post-treatment.To address the challenge of precise delivery of phototherapeutic agents to lesion sites,this thesis developed an NIR light-responsive polyvinyl alcohol（PVA）microneedle（MNs）delivery system.The unique tip structure and mechanical strength of MNs allow them to penetrate local biological barriers,enhancing the delivery of phototherapeutic agents.The phototherapeutic agent,multifunctional porphyrin-like metal-centered nanoparticles（PMCS）,derived from metal-organic frameworks,possesses both NIR responsiveness and enzyme-like catalytic activity.PMCS are uniformly loaded into the MNs system using polydimethylsiloxane molds,forming PMCS@MNs,which demonstrates higher photothermal conversion efficiency than PMCS in water dispersion.In vitro delivery experiments confirmed successful delivery of PMCS by MNs,with enhanced penetration and diffusion under NIR light.The superior photothermal performance of PMCS@MNs under NIR irradiation facilitates the formation of a liquid band-aid,preventing external contaminants from infecting the wound,reducing the risk of secondary infection,and maintaining a moist environment to accelerate wound healing.Antibacterial mechanism studies show that PMCS,through combined photothermal/photodynamic and enzyme-like catalytic activities,disrupts bacterial membrane integrity,induces leakage of K⁺and DNA,and interferes with bacterial protein and ATP synthesis.PMCS@MNs demonstrate excellent NIR-responsive antibacterial effects both in vitro and in vivo,with antibacterial rates of 99.1%and 92.9%,respectively.This system also effectively accelerates wound healing and significantly downregulate inflammatory cytokine expression at the wound site.Compared to commercial band-aids,the PMCS@MNs liquid band-aid exhibits superior wound management performance.In summary,this thesis addresses key challenges that limit the performance and application of phototherapeutic agents.Through the aforementioned work,it offers new research insights and technical means for the structural design,property modulation,and rational delivery of NIR light-responsive phototherapeutic agents.