查看更多>>摘要：Specific tumor-targeted gene delivery remains an unsolved therapeutic issue due to aberrant vascularization in tumor microenvironment(TME).Some bacteria exhibit spontaneous chemotaxis to-ward the anaerobic and immune-suppressive TME,which makes them ideal natural vehicles for cancer gene therapy.Here,we conjugated ZIF-8 metal-organic frameworks encapsulating eukaryotic murine interleukin 2(Il2)expression plasmid onto the surface of VNP20009,an attenuated Salmonella typhimur-ium strain with well-documented anti-cancer activity,and constructed a TME-targeted Il2 delivery system named Il2/ZIF-8@Salmonella.Both in vitro and in vivo experiments demonstrated that Il2/ZIF-8@Sal-monella maintained the tumor-targeting feature of bacteria,and could be effectively phagocytosed by in-tratumoral macrophages,thus leading to the expression and secretion of IL2 in TME.The detailed analysis of tumor immune microenvironment(TIME)showed that one dose of combinatorial Il2/ZIF-8@Salmonella achieved synergistic actions on a potent remodeling of TIME,marked by the activation of cytotoxic T cells and M1-polarization of macrophages in TME,thus leading to significant anti-tumor effects in melanoma,orthotopic hepatocellular carcinoma,and pulmonary metastasis models.More importantly,Il2/ZIF-8@Salmonella exhibited high safety to major organs and hematopoietic systems.Taken together,we report a novel plasmid/ZIF-8@Salmonella system that simultaneously achieves effec-tive TME-targeted delivery of therapeutic gene,as well as synergistic re-activation of TIME.
查看更多>>摘要：Leber's hereditary optic neuropathy(LHON)is an ocular mitochondrial disease that involves the impairment of mitochondrial complex Ⅰ,which is an important contributor to blindness among young adults across the globe.However,the disorder has no available cures,since the approved drug idebenone for LHON in Europe relies on bypassing complex Ⅰ defects rather than fixing them.Herein,PARKIN mRNA-loaded nanoparticle(mNP)-engineered mitochondria(mNP-Mito)were designed to replace dysfunctional mitochondria with the delivery of exogenous mitochondria,normalizing the function of complex Ⅰ for treating LHON.The mNP-Mito facilitated the supplementation of healthy mitochondria containing functional complex Ⅰ via mitochondrial transfer,along with the elimination of dysfunctional mitochondria with impaired complex Ⅰ via an enhanced PARKIN-mediated mitophagy process.In a mouse model induced with a complex Ⅰ inhibitor(rotenone,Rot),mNP-Mito enhanced the presence of healthy mitochondria and exhibited a sharp increase in complex Ⅰ activity(76.5％)compared to the group exposed to Rot damage(29.5％),which greatly promoted the restoration of ATP generation and mitiga-tion of ocular mitochondrial disease-related phenotypes.This study highlights the significance of nanoen-gineered mitochondria as a promising and feasible tool for the replacement of dysfunctional mitochondria and the repair of mitochondrial function in mitochondrial disease therapies.
查看更多>>摘要：The pathophysiology of sepsis is characterized by a systemic inflammatory response to infec-tion;however,the cytokine blockade that targets a specific early inflammatory mediator,such as tumor necrosis factor,has shown disappointing results in clinical trials.During sepsis,excessive endotoxins are internalized into the cytoplasm of immune cells,resulting in dysregulated pyroptotic cell death,which induces the leakage of late mediator alarmins such as HMGB1 and PTX3.As late mediators of lethal sepsis,overwhelming amounts of alarmins bind to high-affinity TLR4/MD2 and low-affinity RAGE re-ceptors,thereby amplifying inflammation during early-stage sepsis.In this study,we developed a novel alarmin/receptor-targeting system using a TLR4/MD2/RAGE-blocking peptide(TMR peptide)derived from the HMGB1/PTX3-receptors interacting motifs.The TMR peptide successfully attenuated HMGB1/PTX3-and LPS-mediated inflammatory cytokine production by impairing its interactions with TLR4 and RAGE.Moreover,we developed TMR peptide-conjugated liposomes(TMR-Lipo)to improve the peptide pharmacokinetics.In combination therapy,moderately antibiotic-loaded TMR-Lipo demon-strated a significant therapeutic effect in a mouse model of cecal ligation-and puncture-induced sepsis.The identification of these peptides will pave the way for the development of novel pharmacological tools for sepsis therapy.
查看更多>>摘要：The neurovascular unit(NVU)is highly responsible for cerebral homeostasis and its dysfunc-tion emerges as a critical contributor to Alzheimer's disease(AD)pathology.Hence,rescuing NVU dysfunction might be a viable approach to AD treatments.Here,we fabricated a self-regulated muti-func-tional nano-modulator(siR/PIO@RP)that can intelligently navigate to damaged blood-brain barrier and release therapeutical cargoes for synergetic AD therapy.The resulting siR/PIO@RP enables self-regulation of its distribution in accordance with the physio/pathological state(low/high RAGE expression)of the target site via a feedback loop.siR/PIO@RP is capable of performing intricate tasks and goes beyond the capabilities of single-target therapeutic agents utilized in AD therapy,such as reducing cerebral Aβ load,relieving neuroinflammation,and alleviating the dysfunction of NVU.Overall,the current study provides proof of concept that normalizing NVU holds promise as a means of alleviating AD symptoms.
查看更多>>摘要：Combination therapy with checkpoint inhibitors blocks inhibitory immune cell signaling and improves clinical responses to anticancer treatments.However,continued development of innovative and controllable delivery systems for immune-stimulating agents is necessary to optimize clinical responses.Herein,we engineered Salmonella to deliver recombinant granulocyte macrophage colony stimulating factor(GM-CSF)in a controllable manner for combination treatment with a programmed death-ligand 1(PD-L1)inhibitor.The engineered Salmonella enabled delivery of recombinant GM-CSF into mouse tumors,activating recruitment of immune cells,such as M1-polarized macrophages,dendritic cells,and CD8+T cells.Combination treatment with the PD-L1 inhibitor and engineered Salmonella increased the survival rate of tumor-bearing mice by 25％.New tumor growth was strongly suppressed,and visible tumors disappeared at 120 days post-infection(dpi)in mice rechallenged with additional tumor implantation at 100 dpi.The number of memory T cells increased＞2-fold in tumor-rechallenged mice.Our findings demonstrate superiority of the engineered Salmonella as a cancer therapeutic agent with pre-cise targeting ability,immune-boosting activity,and ease of combination with other therapeutics.
查看更多>>摘要：The orphan nuclear receptor Nur77 is emerging as an attractive target for cancer therapy,and activating Nur77's non-genotypic anticancer function has demonstrated strong therapeutic potential.However,few Nur77 site B ligands have been identified as excellent anticancer compounds.There are no co-crystal structures of effective anticancer agents at Nur77 site B,which greatly limits the development of novel Nur77 site B ligands.Moreover,the lack of pharmaceutical ligands restricts Nur77's therapeutic proof of concept.Herein,we developed a first-in-class Nur77 site B ligand(NB1)that significantly inhibited cancer cells by mediating the Nur77/Bcl-2-related apoptotic effect at mitochondria.The X-ray crystallography suggests that NB1 is bound to the Nur77 site B with a distinct binding mode.Importantly,NB1 showed favorable pharmacokinetic profiles and safety,as evidenced by its good oral bioavailability in rats and lack of mortality,bodyweight loss,and pathological damage at the 512.0 mg/kg dose in mice.Furthermore,oral administration of NB1 demonstrated remarkable in vivo anticancer efficacy in an MDA-MB-231 xenograft model.Together,our work discovers NB1 as a new generation Nur77 ligand that activates the Nur77/Bcl-2 apoptotic pathway with a safe and effective cancer therapeutic potency.
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