Ha Eun ShinJun-Hyeok HanSeungyong ShinGa-Hyun Bae...
3169-3183页
查看更多>>摘要：Optimum genetic delivery for modulating target genes to diseased tissue is a major obstacle for profitable gene therapy.Lipid nanoparticles(LNPs),considered a prospective vehicle for nucleic acid delivery,have demonstrated efficacy in human use during the COVID-19 pandemic.This study introduces a novel biomaterial-based platform,M1-polarized macrophage-derived cellular nanovesicle-coated LNPs(M1-C-LNPs),specifically engineered for a combined gene-immunotherapy approach against solid tu-mor.The dual-function system of M1-C-LNPs encapsulates Bcl2-targeting siRNA within LNPs and immune-modulating cytokines within M1 macrophage-derived cellular nanovesicles(M1-NVs),effectively facilitating apoptosis in cancer cells without impacting T and NK cells,which activate the in-tratumoral immune response to promote granule-mediating killing for solid tumor eradication.Enhanced retention within tumor was observed upon intratumoral administration of M1-C-LNPs,owing to the pres-ence of adhesion molecules on M1-NVs,thereby contributing to superior tumor growth inhibition.These findings represent a promising strategy for the development of targeted and effective nanoparticle-based cancer genetic-immunotherapy,with significant implications for advancing biomaterial use in cancer therapeutics.
查看更多>>摘要：Helicobacter pylori(H.pylori)infection remains the leading cause of gastric adenocarci-noma,and its eradication primarily relies on the prolonged and intensive use of two antibiotics.However,antibiotic resistance has become a compelling health issue,leading to H.pylori eradication treatment failure worldwide.Additionally,the powerlessness of antibiotics against biofilms,as well as intracellular H.pylori and the long-term damage of antibiotics to the intestinal microbiota,have also created an urgent demand for antibiotic-free approaches.Herein,we describe an antibiotic-free,multifunctional copper-organic framework(HKUST-1)platform encased in a lipid layer comprising phosphatidic acid(PA),rhamnolipid(RHL),and cholesterol(CHOL),enveloped in chitosan(CS),and loaded in an ascorbyl palmitate(AP)hydrogel:AP@CS@Lip@HKUST-l.This platform targets inflammatory sites where H.pylori aggregates through electrostatic attraction.Then,hydrolysis by matrix metalloproteinases(MMPs)releases CS-encased nanoparticles,disrupting bacterial urease activity and membrane integrity.Addition-ally,RHL disperses biofilms,while PA promotes lysosomal acidification and activates host autophagy,enabling clearance of intracellular H.pylori.Furthermore,AP@CS@Lip@HKUST-1 alleviates inflam-mation and enhances mucosal repair through delayed Cu2+release while preserving the intestinal micro-biota.Collectively,this platform presents an advanced therapeutic strategy for eradicating persistent H.pylori infection without inducing drug resistance.
查看更多>>摘要：Combination immunotherapy has shown promising potential for enhancing the objective response rate compared to immune checkpoint blockade(ICB)monotherapy.However,combination ther-apy with multi-drugs is limited by the different properties of the agents and inconsistent synergistic tar-geted delivery.Herein,based on a universal triterpene template and the anticancer active agent ursolic acid(UA),a cytomembrane-coated biomimetic delivery nanoplatform(UR@M)prepared by the self-assembly of a PD-L1 targeted CRISPR/Cas9 system and UA was designed for hepatocellular carcinoma(HCC)treatment.UR@M showed enhanced tumor accumulation in vivo with homologous tumor target-ing,and CRISPR in the nanosystem exhibited potent gene-editing efficiency of 76.53％in vitro and 62.42％in vivo with no off-target effects.UA activated the natural immune system through the TLR-2-MyD88-TRAF6 pathway,which synergistically enhanced the proliferation of natural killer cells and dendritic cells and realized excellent immune cytotoxic T cell infiltration by combining with the ICB of PD-L1.The strategy of work along both lines based on innate immune and adaptive immunity displayed a significant effect in tumor regression.Overall,the UA-templated strategy"killed three birds with one stone"by establishing a self-assembly nanosystem,inducing tumor cell death,and promoting synergistic immunostimulation for HCC treatment.
查看更多>>摘要：Current cytotoxic T lymphocyte(CTL)activating immunotherapy requires a major histocom-patibility complex Ⅰ(MHC-Ⅰ)-mediated presentation of tumor-associated antigens,which malfunctions in around half of patients with triple-negative breast cancer(TNBC).Here,we create a LCL161-loaded macrophage membrane decorated nanoparticle(LMN)for immunotherapy of MHC-Ⅰ-deficient TNBC.SIRPα on the macrophage membrane helps LMNs recognize CD47-expressing cancer cells for targeted delivery of LCL161,which induces the release of high mobility group protein 1 and proinflammatory cytokines from cancer cells.The released cytokines and high mobility group protein 1 activate antitumor immunity by increasing the intratumoral density of the phagocytic macrophage subtype by 15 times and elevating the intratumoral concentration of CTL lymphotoxin by 4.6 folds.LMNs also block CD47-mediated phagocytosis suppression.LMNs inhibit the growth of MHC-Ⅰ-deficient TNBC tumors,as well as those resistant to combined therapy of anti-PDL1 antibody and albumin-bound paclitaxel,and prolong the survival of animals,during which process CTLs also play important roles.This macrophage membrane-decorated nanoparticle presents a generalizable platform for increasing macrophage-mediated antitumor immunity for effective immunotherapy of MHC-Ⅰ-deficient cancers.
查看更多>>摘要：Insufficient therapeutic strategies for acute kidney injury(AKI)necessitate precision ther-apy targeting its pathogenesis.This study reveals the new mechanism of the marine-derived anti-AKI agent,piericidin glycoside S14,targeting peroxiredoxin 1(PRDX1).By binding to Cys83 of PRDX1 and augmenting its peroxidase activity,S14 alleviates kidney injury efficiently in Prdx1-overexpres-sion(Prdx1-OE)mice.Besides,S14 also increases PRDX1 nuclear translocation and directly activates the Nrf2/HO-1/NQO1 pathway to inhibit ROS production.Due to the limited druggability of S14 with low bioavailability(2.6％)and poor renal distribution,a pH-sensitive kidney-targeting dodecanamine-chitosan nanoparticle system is constructed to load S14 for precise treatment of AKI.L-Serine conju-gation to chitosan imparts specificity to kidney injury molecule-1(Kim-1)-overexpressed cells.The developed S14-nanodrug exhibits higher therapeutic efficiency by improving the in vivo behavior of S14 significantly.By encapsulation with micelles,the AUC0-t,half-life time,and renal distribution of S14 increase 2.5-,1.8-,and 3.1-fold,respectively.The main factors contributing to the improved druggability of S14 nanodrugs include the lower metabolic elimination rate and UDP-glycosyltransferase(UGT)-mediated biotransformation.In summary,this study identifies a new ther-apeutic target for the marine-derived anti-AKI agent while enhancing its ADME properties and drugg-ability through nanotechnology,thereby driving advancements in marine drug development for AKI.
查看更多>>摘要：Selective activation of Pt(Ⅳ)prodrugs within tumors has emerged as a promising strategy in tumor treatment.Although progress has been made with photo-and ultrasound-activated Pt(Ⅳ)prodrugs,concerns remain over the non-specific activation of photosensitizers(PS)and the potential for phototox-icity and chemical toxicity.In this study,a sequential dual-locked Pt(Ⅳ)nano-prodrug that can be acti-vated by both the acidic tumor microenvironment and light was developed.The Pt(Ⅳ)prodrug was prepared by conjugating PS-locked Pt(Ⅳ)to a polymeric core,which was then chelated with metallo iron to lock its photoactivity and form a metallo-nano prodrug.Under acidic tumor microenvironment condi-tions,the metallo-nano prodrug undergoes dissociation of iron,triggering a reduction process in oxalipla-tin under light irradiation,resulting in the activation of both chemotherapy and photodynamic therapy(PDT).Additionally,the prodrug could induce metallo-triggered ferroptosis and polarization of tumor-associated macrophages(TAM),thereby enhancing tumor inhibition.The dual-lock strategy employed in a nanoparticle delivery system represents an expansion in the application of platinum-based anticancer drugs,making it a promising new direction in cancer treatment.
查看更多>>摘要：The drugs extending healthspan in clinic have always been searched.Nitazoxanide is an FDA-approved clinical antiprotozoal drug.Nitazoxanide is rapidly metabolized to tizoxanide after absorption in vivo.Our previous studies find that nitazoxanide and its metabolite tizoxanide induce mild mitochondrial uncoupling and activate cellular AMPK,oral nitazoxanide protects against experimental hyperlipidemia,hepatic steatosis,and atherosclerosis.Here,we demonstrate that both nitazoxanide and tizoxanide extend the lifespan and healthspan of Caenorhabditis elegans through Akt/AMPK/sir 2.1/daf 16 pathway.Additionally,both nitazoxanide and tizoxanide improve high glucose-induced short-ening of C.elegans lifespan.Nitazoxanide has been a clinical drug with a good safety profile,we suggest that it is a novel anti-aging drug.
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