Ca&Mn dual-ion hybrid nanostimulator boosting anti-tumor immunity via ferroptosis and innate immunity awakening

Limited by low tumor immunogenicity and the immunosuppressive tumor microenvironment(TME),triple-negative breast cancer(TNBC)has been poorly responsive to immunotherapy so far.Herein,a Ca&Mn dual-ion hybrid nanostimulator(CMS)is constructed to enhance anti-tumor immunity through ferroptosis inducing and innate immunity awakening,which can serve as a ferroptosis inducer and immunoadjuvant for TNBC concurrently.On one hand,glutathione(GSH)depletion and reactive oxygen species(ROS)generation can be achieved due to the mixed valence state of Mn in CMS.On the other hand,as an exotic Ca2+supplier,CMS causes mitochondrial Ca2+overload,which further amplifies the oxidative stress.Significantly,tumor cells undergo ferroptosis because of the inactivation of glutathione peroxidase 4(GPX4)and accumulation of lipid peroxidation(LPO).More impressively,CMS can act as an immunoadjuvant to awaken innate immunity by alleviating intra-tumor hypoxia and Mn2+-induced activation of the STING signaling pathway,which promotes polarization of tumor-associated macrophages(TAMs)and activation of dendritic cells(DCs)for antigen presentation and subsequent infiltration of tumor-specific cytotoxic T lymphocytes(CTLs)into tumor tissues.Taken together,this work demonstrates a novel strategy of simultaneously inducing ferroptosis and awakening innate immunity,offering a new perspective for effective tumor immunotherapy of TNBC.

Enzyme-like biomimetic oral-agent enabling modulating gut microbiota and restoring redox homeostasis to treat inflammatory bowel disease

Reactive oxygen species(ROS),immune dysregulation-induced inflammatory outbreaks and microbial imbalance play critical roles in the development of inflammatory bowel disease(IBD).Herein,a novel enzyme-like biomimetic oral-agent ZnPBA@YCW has been developed,using yeast cell wall(YCW)as the outer shell and zinc-doped Prussian blue analogue(ZnPBA)nanozyme inside.When orally administered,the ZnPBA@YCW is able to adhere to Escherichia coli occupying the ecological niche in IBD and subsequently release the ZnPBA nanozyme for removal of E.coli,meanwhile exhibiting improved intestinal epithelial barrier repair.Moreover,it is found that the ZnPBA nanozyme exhibits remarkable capability in restoring redox homeostasis by scavenging ROS and inhibiting NF-κB signaling pathway.More importantly,the 16S ribosomal RNA gene sequencing results indicate that post-oral of ZnPBA@YCW can effectively regulate gut microbiota by enhancing the bacterial richness and diversity,significantly increasing the abundance of probiotics with anti-inflammatory phenotype while downgrading pathogenic E.coli to the same level as normal mice.Such a novel nanomedicine provides a new idea for efficient treating those ROS-mediated diseases accompanying with flora disorders.