Search

Anaerobic bacteria and facultative anaerobe are usually used as delivery carriers of antitumor drugs because of their tumor hypoxia targeting and antitumor immune activation abilities, but suffer from dose-dependent systemic side effects. Here, engineered probiotics Nissle 1917 (EcN-T) were constructed for in-situ synthesis of melanin in tumor region for enhanced photothermal therapy (PTT) combining with immunotherapy. By means of genetic engineering, EcN-T that could highly express tyrosinase under near-infrared (NIR) light irradiation were constructed. Due to their intrinsic tumor hypoxia targeting, EcN-T could accumulate and rapidly proliferate in tumor region after intravenous injection. Tyrosinase expression for the following melanin biosynthesis within tumor could be initiated upon NIR exposure. Hyperbaric oxygen treatment facilitated the oxidation of tyrosine to promote the generation of melanin in situ, giving robust photothermal performance to induce immunogenic tumor cell death. Assited by immunostimulatory responses of EcN, maturation of dendritic cells and priming of cytotoxic T cells were largely promoted in tumor tissue, resulting in significant inhibition of tumor growth and recurrence. This bacteria-mediated combined therapeutic strategy showed high efficacy and good safety. By means of genetic engineering and synthetic biology, engineered probiotics Nissle 1917 (EcN-T) which show excellent tumor targeting and proliferation abilities are constructed for in-situ synthesis of melanin in tumor region induced by NIR light irradiation and HBO treating. Upon light exposure, considerable heat can be generated to induce immunogenic tumor cell death. Assited by immunostimulatory responses of EcN, maturation of dendritic cells and priming of cytotoxic T cells are largely promoted in tumor tissue, giving significant inhibition of tumor growth and recurrence. [Display omitted] • Engineered probiotics Nissle 1917 can intracellularly produce melanin with excellent photothermal performance. • Engineered probiotics Nissle 1917 can rapidly proliferate and homogenously distribute in tumor region. • Melanin biosynthesis within tumor can be initiated upon external NIR exposure. • Hyperbaric oxygen can promote the generation of melanin within tumor. [ABSTRACT FROM AUTHOR]

• Probiotic-derived selenium (Se) nanoparticles acted as the immune adjuvant. • HBO effectively promoted the Se-mediated O 2 – generation to boost tumor CDT. • HBO largely ameliorated the immunosuppressive tumor microenvironment. Chemodynamic therapy (CDT) was a promising approach to enhance the immunogenicity of tumor cells for potentiating immune checkpoint blockade (ICB) therapy, but usually suffered from hypoxia and immunosuppressive tumor microenvironment. Herein, we developed a hyperbaric oxygen (HBO)-strengthened CDT-nanoadjuvants platform (Se@OMV-GOx-HA) by modifying probiotic-derived selenium (Se) nanoparticles with glucose oxidase (GOx) and hyaluronic acid (HA) to boost αPD-L1-medaited ICB therapy against breast cancer. In the presence of H 2 O 2 and glutathione (GSH), Se@OMV acted as nanoenzyme to mediate the electron transfer from GSH to O 2 giving O 2 –, while GOx catalyzed the production of H 2 O 2. Synergistically, HBO effectively improved tumor hypoxia to foster GOx-catalyzed oxidation of glucose to H 2 O 2 , then provided the essential fuels including H 2 O 2 and O 2 for Se-mediated O 2 – generation, causing strong immunogenic cell death (ICD) effect to enhance the immunogenicity of tumor cells. Under co-stimulation by Se@OMV acting as immunoadjuvants, maturation of dendritic cells and priming of cytotoxic T cells were largely promoted. Assisted by HBO, infiltration of cytotoxic T cells in mice tumor was significantly improved, which not only generated long-term antitumor immune memory, but largely boosted αPD-L1-medaited ICB therapy. Given the clinical available of HBO, this nanosystem has great clinical translation potential for cancer CDT/immunotherapy. [ABSTRACT FROM AUTHOR]

Cytotoxic T lymphocyte (CTL), a key effector cell in aplastic anemia (AA) immune injury, is shown to be a potential target for AA drug therapy. However, there is no candidate for this target till now. Oriented by the inhibition activity of CTL and macrophage derived nitric oxide (NO), a series of novel sinomenine derivatives on rings A and C are designed, synthesized and screened. Among them, compound 3a demonstrates the best inhibitory activity on CTL with an IC 50 value of 2.3 μM, and a 97.1% inhibiton rate on macrophage NO production without significant cytotoxicity. Further, compound 3a exhibits substantial therapeutic efficacy on immune-mediated BM failure in AA model mice by improving the symptoms of anemia and the function of BM hematopoiesis, and shows more advantages in life quality improving than cyclosporine A (CsA). Its efficacy on AA at least partly comes from targeting on activated cluster of differentiation (CD)8+ T cell. Additionally, 3a also shows much less toxicity (LD 50 > 10.0 g/kg) than sinomenine (LD 50 = 1.1 g/kg) in preliminary acute toxicity assessment in mice, and has a low risk to inhibit hERG to cause cardiotoxicity. These results indicate that compound 3a merits further investigation for AA treatment by targeting on CTL. [Display omitted] • A series of novel sinomenine derivatives are designed and synthesized. • 3a shows the best in vitro inhibitory activity. • 3a shows substantial therapeutic efficacy on mice model of aplastic anemia. • The efficacy of 3a at least partly comes from targeting on activated CD8+ T cell. • 3a shows good safety in vivo. [ABSTRACT FROM AUTHOR]