Biomimetic Gold Nanorods For Controlled Release No To Reprogram Immunosuppressive Microenvironment And Enhance Anticancer Photoimmunotherapy

Cancer photoimmunotherapy is becoming a very promising therapeutic modality base on the effect of local tumor ablation in photothermal therapy（PTT）and the induced immunogenic cell death to activate the body’s immune response against the residual tumor cells.However,selection and delivery of a proper photothermal agent into the target tumor,and the complex immunosuppressive tumor microenvironment（such as hypoxia,insufficient immune cell infiltration）were the main challenges of efficient cancer photoimmunotherapy.Photothermal agent triggered by the second region of near-infrared laser（e.g.NIR-II,900-1700 nm）is very beneficial for deep tumor killing because of that NIR-II laser owns higher tissue penetration depth.Compared with the traditional drug delivery system,membrane biomimetic delivery nanosystem with proper modification could realize the penetration and accumulation of photothermal agent in the inner part of tumor.On the other hand,NO emerges as a potent candidate to promote angiogenesis,alleviate tumor hypoxia and reprogram the tumor immunosuppressive microenvironment.Therefore,it is hypothesized that constructing a biomimetic photothermal nanoagent with the function of response to NIR-II laser,targeting and penetrating into tumor center,delivery NO to reprogram tumor immunosuppressive microenvironment could achieve the high synergy of photoimmunotherapy against the primary and metastasized tumors.Based on the above,this thesis designed a kind of multifunctional biomimic gold nanorod（denoted as GNR-SNO@MMT）with the aim to realize deep tumor targeting ＆penetrating,phtothermal ablation the tumor cells under NIR-II laser activation,photothermally controlled releasing NO to reprogram tumor immunosuppressive microenvironment and enhancing the efficiency of photoimmunotherapy.S-nitrosothiol grafted gold nanorods were camouflaged with macrophage membrane and further modified with the tumor-penetrating peptide tLyp-1 to yield GNR-SNO@MMT.It was characterized by transmission electron microscopy,dynamic light scattering,UV-visibleNIR absorption spectroscopy,etc.Under laser irradiation（1064 nm）,it had excellent efficiency of photothermal conversion and NO releasing.It could target and penetrate into deep tumor cell layers.In vivo data of 4T1 mammary tumor model verified its effective accumulation in tumor sites and can effectively inhibited tumor growth.Moreover,GNRSNO@MMT could effectively relieve tumor hypoxia,enhance the blood perfusion and reprogram the tumor immunosuppressive microenvironment（e.g.decreasing PD-L1,repolalizing TAM）.Finally,analysis of the liver function,kidney function and organ H＆E staining at the end of treatment proved that GNR-SNO@MMT was relatively biosafe.In summary,this thesis demonstrated that the engineered biomimetic nanosystem GNR-SNO@MMT is a potent candidate for the new type of cancer photoimmuno therapy against cancer with the external NIR-II laser activation and the internal interfere of tumor microenvironment.