Self-sufficient nanoparticles with dual-enzyme activity trigger radical storms and activate cascade-amplified antitumor immunologic responses

Radiotherapy(RT) can potentially induce systemic immune responses by initiating immunogenic cell death(ICD) of tumor cells.However,RT-induced antitumor immunologic responses are sporadic and insufficient against cancer metastases.Herein,we construct multifunctional self-sufficient nanoparticles(MARS) with dual-enzyme activity(GOx and peroxidase-like) to trigger radical storms and activate the cascade-amplified systemic immune responses to suppress both local tumors and metastatic relapse.In addition to limiting the Warburg effect to actualize starvation therapy,MARS catalyzes glucose to produce hydrogen peroxide(H_(2)O_(2)),which is then used in the Cu^(+)-mediated Fenton-like reaction and RT sensitization.RT and chemodynamic therapy produce reactive oxygen species in the form of radical storms,which have a robust ICD impact on mobilizing the immune system.Thus,when MARS is combined with RT,potent systemic antitumor immunity can be generated by activating antigen-presenting cells,promoting dendritic cells maturation,increasing the infiltration of cytotoxic T lymphocytes,and reprogramming the immuno suppre ssive tumor microenvironment.Furthermore,the synergistic therapy of RT and MARS effectively suppresses local tumor growth,increases mouse longevity,and results in a 90% reduction in lung metastasis and postoperative recurrence.Overall,we provide a viable approach to treating cancer by inducing radical storms and activating cascade-amplified systemic immunity.

Chemo-immunotherapy by dual-enzyme responsive peptide self-assembling abolish melanoma

Herein,we designed Comp.1 to simultaneously respond to two enzymes:alkaline phosphatase and matrix metalloproteinase 2,which is commonly found in highly malignant cancer cell lines containing B16-F10 murine melanoma cells and CT26 murine colon carcinoma cells.We used the regional differences in the expression levels of dual-markers to accurately release immune molecule IND into tumor microenvironment for the activation of anti-tumor related immune effects,while in-situ self-assembly occurs.The dual-enzyme response process can further regulate the peptide precursors’self-assembly in the form of short rod-shaped nanofibers,enabling the delivery of the loaded chemotherapeutic drug HCPT into the cancer cells and further allowing the peptide assemblies to escape from lysosomes and return to cytoplasm in the form of tiny nanoparticles to induce apoptosis of cancer cells.This process does not occur in the single-positive breast cancer cell line MCF-7 or the normal hepatocytes cell line LO2,indicating the selectivity of the cancer cells exhibited using our strategy.In vivo studies revealed that Comp.1 can effectively cooperate with chemotherapy to enhance the immunotherapy effect and induce immune responses associated with elevated pro-inflammatory cytokines in vivo to inhibit malignant tumors growth.Our dual-enzyme responsive chemo-immunotherapy strategy feasible in anti-tumor treatment,provides a new avenue for regulating peptide self-assembly to adapt to diverse tumor properties and may eventually be used for the development of novel multifunctional anti-tumor nanomedicines.

Enhanced production of cytidine 5'-monophosphate using biocatalysis of di-enzymes immobilized on amino-functionalized sepharose

Cytidine 5'-monophosphate(5'-CMP)is an essential nucleotide for additives.In this study,enhanced production of 5'-CMP was realized by the transformation of cytidine using co-immobilized di-enzymes,uridine-cytidine kinase(UCK)and acetate kinase(AcK).The immobilization yield of the enzyme had a clear correlation with the surface charges as zeta potential(ξ).Among them,ε-polylysinefunctionalized sepharose(SA-EPL,ξ=9.31 m V)showed high immobilization yield(78.8%),which was4.9-fold than that of nitrilotriacetic acid functionalized sepharose(SA-NTA,ξ=-12.6 m V).The residual activity of affinity co-immobilized enzyme(EPL-Ni/EPL@Ac K-UCK)was higher than 70.6%after recycled 10 times.Thus,this study provides an effective approach for the production of 5'-CMP with the advantages of low adenosine 5'-triphosphate(ATP)consumption,reduced side reactions,and improved reusability by co-immobilized UCK and Ac K on the functionalized Sepharose.