Designing And Constructing Stimuli-Responsive Nanosystems For Regulation Of Cell Fate

Cell is the basic unit of morphological structure and function of an organism.Cellbased study is the basis to understand life science and the driving force for the development of modern medicine.A large number of life activities occur at the cell level,mainly including cell growth,proliferation,differentiation and death.Therefore,in-depth study of cell life activities is of great significance for revealing the mechanism of disease occurrence and exploiting individualized diagnosis and treatment.Based on the rapid development of nanofunctional materials and fabrication techniques,various stimulus-responsive systems have been developed.Under the guidance of endogenous or exogenous stimuli,these intelligent systems can effectively regulate cell signal transduction and control cell fate.Undoubtedly,this provides powerful tools for biomedical application and revealing life processes.The present thesis designs and constructs a series of stimuli-responsive platforms to achieve the regulation of cell behavior,including inhibiting the growth and proliferation of cancer cells and bacteria,and regulating the differentiation of mesenchymal stem cells.The main conclusions are summarized as follows:1.An intelligent nanocarrier(ZDHD),which can release HAase in response to the acidic tumor microenvironment(pH 6.5)and perform a strong neighboring effect with size reduction to accomplish drug deep tumor penetration in vivo,is reported.In this design,hyaluronidase(HAase)is encapsulated on the surfaces of doxorubicin(DOX)preloaded ZnO-DOX nanoparticles(NPs)using a charge convertible polymer PEGPAH-DMMA.The polymer can release HAase to degrade hyaluronic acid(HA)in the tumor extracellular matrix(ECM,pH 6.5).ZnO-DOX NPs can release DOX in lysosomes(pH 4.5)to induce cell apoptosis,and exert a neighboring effect with size reduction to infect neighboring cells.The hierarchical targeted release of HAase and drugs is demonstrated to enhance antitumor effect of ZDHD in vivo.2.Inspired by neutrophils and natural ultrasensitive response circuits,here we design and construct a tumor discrimination nanodevice based on the differential histone H1 isoform expression.In this nanodevice,neutrophil membrane camouflage and glutathione(GSH)-unlocking effect on Fe-porphyrin metal-organic framework structure ensure primary selectivity to cancer cells.The released porcine pancreatic elastase(PPE)simulates neutrophils’ action by proteolytically liberating the CD95 death domain(DD)which interacts with histone H1 in cytosol.Meanwhile,nuclear localization signal(NLS)peptide-tagged porphyrin(porphyrin-NLS)as an actuator for positive feedback loop of histone H1 translocation outputs exponentially amplified histone H1 nucleo-cytoplasmic translocation by producing singlet oxygen(1O2)as input signal in the nucleus under laser irradiation.Thus,the enhanced CD95 DD-H1.0 interaction promotes cancer cell killing.The overexpressed histone H1 isoform in cancer cells ensures the selectivity of our nanodevice to cancer cells.As a result,our design can not only inhibit primary tumor growth,but also induce adaptive T-cell response-mediated abscopal effect against distal tumors,which has been demonstrated by in vivo studies.3.A near-infrared(NIR)light-driven nanoswimmer(HSMV)is designed.Under NIR light irradiation,HSMV performs efficient self-propulsion and penetrates into the biofilm within 5 min due to photothermal conversion of asymmetrically distributed AuNPs.The localized thermal and thermal-triggered release of vancomycin(Van)lead to an efficient combination of photothermal therapy(PTT)and chemotherapy.The active motion of HSMV increases the effective distance of PTT and also improves the therapeutic index of the antibiotic,allowing HSMV to eliminate biofilm in vitro and in vivo.Simultaneously,the moderate local heat(～45℃)minimizes collateral damage to surrounding healthy tissues.4.We design and synthesize a topologically engineered gold nanoisland for programmed stem cell manipulation,and as an integrated processing chain of therapeutic cells for long-term manipulation of stem cells in vivo.The presentation of topological programming ligands with optimized lateral spacing promotes stem cell adhesion,proliferation,mechanosensing and differentiation.Additionally,the enzyme activity,stable membrane-anchoring and magnetic responsiveness of island guide cell detachment,in suit magnetic labeling and retention,thus ensuring programmed stem cell manipulation in vivo over prolonged time.