Bone microenvironment regulative hydrogels with ROS scavenging and prolonged oxygen-generating for enhancing bone repair

Large bone defects resulting from fractures and disease are a major clinical challenge,being often unable to heal spontaneously by the body’s repair mechanisms.Lines of evidence have shown that hypoxia-induced overproduction of ROS in bone defect region has a major impact on delaying bone regeneration.However,replenishing excess oxygen in a short time cause high oxygen tension that affect the activity of osteoblast precursor cells.Therefore,reasonably restoring the hypoxic condition of bone microenvironment is essential for facilitating bone repair.Herein,we designed ROS scavenging and responsive prolonged oxygen-generating hydrogels(CPP-L/GelMA)as a“bone microenvironment regulative hydrogel”to reverse the hypoxic microenvironment in bone defects region.CPP-L/GelMA hydrogels comprises an antioxidant enzyme catalase(CAT)and ROS-responsive oxygen-releasing nanoparticles(PFC@PLGA/PPS)co-loaded liposome(CCP-L)and GelMA hydrogels.Under hypoxic condition,CPP-L/GelMA can release CAT for degrading hydrogen peroxide to generate oxygen and be triggered by superfluous ROS to continuously release the oxygen for more than 2 weeks.The prolonged oxygen enriched microenvironment generated by CPP-L/GelMA hydrogel significantly enhanced angiogenesis and osteogenesis while inhibited osteoclastogenesis.Finally,CPP-L/GelMA showed excellent bone regeneration effect in a mice skull defect model through the Nrf2-BMAL1-autophagy pathway.Hence,CPP-L/GelMA,as a bone microenvironment regulative hydrogel for bone tissue respiration,can effectively scavenge ROS and provide prolonged oxygen supply according to the demand in bone defect region,possessing of great clinical therapeutic potential.

Fish scale-derived scaffolds with MSCs loading for photothermal therapy of bone defect

Tissue engineering scaffolds have presented effective value in bone repair.However,the integration of the diverse components,complex structures,multifunction to impart the scaffolds with improved applicability is still a challenge.Here,we propose a novel fish-derived scaffold combined with photothermal therapy and mesenchymal stem cells(MSCs)to promote bone regeneration.The fish-derived scaffold is composed of the decellularized fish scale and gelatin methacrylate synthesized from fish gelatin(fGelMA),which can promote the proliferation and osteogenesis of MSCs with no obvious immunological rejection.Furthermore,the black phosphorus(BP)nanosheets are incorporated into the fGelMA hydrogel network,which can endow the hydrogel with the capacity of photothermal conversion stimulated by near-infrared(NIR)light.The fish-derived scaffold can promote the osteogenesis process of MSCs with higher expression of osteogenic markers and higher mineralization assisted by the NIR light in vitro.The regeneration of mice calvarial defect has also been accelerated by the scaffold with photothermal therapy and MSCs.These results suggest that the fish-derived scaffold,photothermal therapy,MSCs-based regenerative therapy is a promising clinical strategy in bone regeneration.

Nanoenzyme engineered neutrophil-derived exosomes attenuate joint injury in advanced rheumatoid arthritis via regulating inflammatory environment

Rheumatoid arthritis(RA)is a chronic inflammatory disease characterized by synovitis and destruction of cartilage,promoted by sustained inflammation.However,current treatments remain unsatisfactory due to lacking of selective and effective strategies for alleviating inflammatory environments in RA joint.Inspired by neutrophil chemotaxis for inflammatory region,we therefore developed neutrophil-derived exosomes functionalized with sub-5 nm ultrasmall Prussian blue nanoparticles(uPB-Exo)via click chemistry,inheriting neutrophil-targeted biological molecules and owning excellent anti-inflammatory properties.uPB-Exo can selectively accumulate in activated fibroblast-like synoviocytes,subsequently neutralizing pro-inflammatory factors,scavenging reactive oxygen species,and alleviating inflammatory stress.In addition,uPB-Exo effectively targeted to inflammatory synovitis,penetrated deeply into the cartilage and real-time visualized inflamed joint through MRI system,leading to precise diagnosis of RA in vivo with high sensitivity and specificity.Particularly,uPB-Exo induced a cascade of anti-inflammatory events via Th17/Treg cell balance regulation,thereby significantly ameliorating joint damage.Therefore,nanoenzyme functionalized exosomes hold the great potential for enhanced treatment of RA in clinic.

Disruption of cyclin D1 degradation leads to the development of mantle cell lymphoma

Cyclin D1 has been recognized as an oncogene due to its abnormal upregulation in different types of cancers.Here,we demonstrated that cyclin D1 is SUMOylated,and we identified Itch as a specific E3 ligase recognizing SUMOylated cyclin D1 and mediating SUMO-induced ubiquitination and proteasome degradation of cyclin D1.We generated cyclin D1 mutant mice with mutations in the SUMOylation site,phosphorylation site,or both sites of cyclin D1,and found that double mutant mice developed a Mantle cell lymphoma(MCL)-like phenotype.We showed that arsenic trioxide(ATO)enhances cyclin D1 SUMOylation-mediated degradation through inhibition of cyclin D1 deSUMOylation enzymes,leading to MCL cell apoptosis.Treatment of severe combined immunodeficiency(SCID)mice grafted with MCL cells with ATO resulted in a significant reduction in tumor growth.In this study,we provide novel insights into the mechanisms of MCL tumor development and cyclin D1 regulation and discover a new strategy for MCL treatment.