Inhibited immune response and low levels of delivery restrict starvation cancer therapy efficacy. Here, we report on the co-delivery of glucose oxidase (GOx) and indoleamine 2,3-dioxygenase (IDO) inhibitor 1-methyltryptophan using a metal-organic framework (MOF)-based nanoreactor, showing an amplified release for tumor starvation/oxidation immunotherapy. The nanosystem significantly overcomes the biobarriers associated with tumor penetration and improves the cargo bioavailability owing to the weakly acidic tumor microenvironment-activated charge reversal and size reduction strategy. The nanosystem rapidly disassembles and releases cargoes in response to the intracellular reactive oxygen species (ROS). GOx competitively consumes glucose and generates ROS, further inducing the self-amplifiable MOF disassembly and drug release. The starvation/oxidation combined IDO-blockade immunotherapy not only strengthens the immune response and stimulates the immune memory through the GOx-activated tumor starvation and recruitment of effector T cells, but also effectively relieves the immune tolerance by IDO blocking, remarkably inhibiting the tumor growth and metastasis in vivo.

Current treatments for implant-associated infection remain unsatisfactory due to secondary infection and excessive inflammation, which impairs osseointegration. Herein, an interfacial functionalization strategy is proposed by the integration of a carbon monoxide gas (CO) nanogenerator on titanium implants, followed by covalently grafting arginine-glycine-aspartic acid (RGD) polypeptide. Under near-infrared light (NIR) irradiation, the designed surface displays great light-activatable antibiosis through CO-potentiated mild photothermal therapy. Interestingly, the functionalized surface exerts a CO-mediated anti-inflammatory effect by activating the expression of heme oxygenase (HO-1), and inducing the down-regulation of p38 mitogen-activated protein kinase (MAPK) and nuclear factor kappa B (NFκB) (p50/p65). More importantly, the combination of CO delivery and RGD immobilization drives the polarization of lipopolysaccharide (LPS)-stimulated M1-phenotype macrophages towards anti-inflammatory M2-pheno type through a potentialJanus kinase 1/signal transducer and activator of transcription 6 (JAK1/STAT6) pathway, thereby remodeling the damaged microenvironment into a proregenerative microenvironment. In a rat model of implant-associated infection, the designed surface effectively eliminates the residual bacteria, alleviates the accompanying inflammation and mediates macrophagemediated immunomodulation, resulting in good osteogenesis. Together, these findings are a first report on the therapeutic potential of CO signal in the cascade of immunomodulation-osteogenic differentiation. The functionalized implant may serve as a promising candidate in implant replacement surgeries.

Scientific description about the types, synthesis, functionalization, characterization application, challenges and prospects of nanomaterials in tissue engineering.

No abstract