Privacy-Preserving Large-Scale AI Models for Intelligent Railway Transportation Systems:Hierarchical Poisoning Attacks and Defenses in Federated Learning

The development of Intelligent Railway Transportation Systems necessitates incorporating privacy-preserving mechanisms into AI models to protect sensitive information and enhance system efficiency.Federated learning offers a promising solution by allowing multiple clients to train models collaboratively without sharing private data.However,despite its privacy benefits,federated learning systems are vulnerable to poisoning attacks,where adversaries alter local model parameters on compromised clients and send malicious updates to the server,potentially compromising the global model’s accuracy.In this study,we introduce PMM(Perturbation coefficient Multiplied by Maximum value),a new poisoning attack method that perturbs model updates layer by layer,demonstrating the threat of poisoning attacks faced by federated learning.Extensive experiments across three distinct datasets have demonstrated PMM’s ability to significantly reduce the global model’s accuracy.Additionally,we propose an effective defense method,namely CLBL(Cluster Layer By Layer).Experiment results on three datasets have confirmed CLBL’s effectiveness.

Functionalized lipid nanoparticles modulate the blood-brain barrier and eliminate α-synuclein to repair dopamine neurons

The challenge in the clinical treatment of Parkinson's disease lies in the lack of disease-modifying therapies that can halt or slow down the progression. Peptide drugs, such as exenatide (Exe), with potential disease-modifying efficacy, have difficulty in crossing the blood-brain barrier (BBB) due to their large molecular weight. Herein, we fabricate multi-functionalized lipid nanoparticles (LNP) Lpc-BoSA/CSO with BBB targeting, permeability-increasing and responsive release functions. Borneol is chemically bonded with stearic acid and, as one of the components of Lpc-BoSA/CSO, is used to increase BBB permeability. Immunofluorescence results of brain tissue of 15-month-old C57BL/6 mice show that Lpc-BoSA/CSO disperses across the BBB into brain parenchyma, and the amount is 4.21 times greater than that of conventional LNP. Motor symptoms of mice in Lpc-BoSA/CSO-Exe group are significantly improved, and the content of dopamine is 1.85 times (substantia nigra compacta) and 1.49 times (striatum) that of PD mice. α-Synuclein expression and Lewy bodies deposition are reduced to 51.85% and 44.72% of PD mice, respectively. Immunohistochemical mechanism studies show AKT expression in Lpc-BoSA/CSO-Exe is 4.23 times that of PD mice and GSK-3β expression is reduced to 18.41%. Lpc-BoSA/CSO-Exe could reduce the production of α-synuclein and Lewy bodies through AKT/GSK-3β pathway, and effectively prevent the progressive deterioration of Parkinson's disease. In summary, Lpc-BoSA/CSO-Exe increases the entry of exenatide into brain and promotes its clinical application for Parkinson's disease therapy.

Regulation of pathological blood-brain barrier for intracranial enhanced drug delivery and anti-glioblastoma therapeutics

The blood-brain barrier(BBB)is an essential component in regulating and maintaining the homeostatic microenvironment of the central nervous system(CNS).During the occurrence and development of glioblastoma(GBM),BBB is pathologically destroyed with a marked increase in permeability.Due to the obstruction of the BBB,current strategies for GBM therapeutics still obtain a meager success rate and may lead to systemic toxicity.Moreover,chemotherapy could promote pathological BBB functional restoration,which results in significantly reduced intracerebral transport of therapeutic agents during multiple administrations of GBM and the eventual failure of GBM chemotherapy.The effective delivery of intracerebral drugs still faces severe challenges.However,strategies that regulate the pathological BBB to enhance the transport of therapeutic agents across the barrier may provide new opportunities for the effective and safe treatment of GBM.This article reviews the structure and function of BBB in physiological states,the mechanisms underlying BBB pathological fenestration during the development of GBM,and the therapeutic strategies of GBM based on BBB intervention and medicinal drugs transporting across the BBB.

ROS-responsive nanoparticles targeting inflamed colon for synergistic therapy of inflammatory bowel disease via barrier repair and anti-inflammation

The destruction of the intestinal barrier is likely to cause an increase in intestinal permeability and cause pathological damage.Numerous studies have demonstrated that intestinal barrier function plays an important role in the occurrence and development of inflammatory bowel disease(IBD).Oral administration is the most common route for intestinal diseases.In this study,a synergistic strategy is proposed for IBD management through active barrier repair combined with anti-inflammatory treatment,which can interrupt the pathological process of IBD,resulting in the significantly improved efficacy of existing treatments.Based on the specific pH values and high reactive oxygen species(ROS)levels in inflammatory sites of IBD,an orally administrated ROS-responsive drug delivery system targeting inflamed colon has been designed,and confirmed in vitro and in vivo.The anti-inflammatory drug dexamethasone acetate(Dex)and the barrier function regulator LY294002 are delivered by the synthesized nanocarrier to treat IBD synergistically by inhibiting inflammation and actively repairing the intestinal barrier through tight junctions(TJs).The accumulation of nanocarriers in the inflamed colon and synergistic efficacy has been validated in mice with colitis.In brief,a drug delivery system and a therapeutic strategy for IBD are successfully developed.

Self-oriented central-tumor delivery of legumain-cleavable vehicles governed by circulating monocyte/macrophage for precise tumor enrichment and immune activation

Compressed blood and intratumoral lymphatic vessels induced by proliferated tumor cells and elevated interstitial fluid pressure produce regional hypoxic and necrotic region within tumors,which severely reduced the accessibility of immunogenic cell death(ICD)related drugs and immune-related cells.Herein,the strategy of self-oriented deep tumor delivery by circulating monocyte/macrophage was proposed.Briefly,CS-AI including an indoleamine 2,3-dioxygenase(IDO)inhibitor indoximod(IND)and hydrophilic chitosan(CSO)linked with alanine-alanine-asparagine(AAN)was prepared,which could be selectively cleaved by legumain overexpressed in macrophages and promote the collapse in structure.Then,CS-AI was modified with mannose on the surface and further encapsulated the ICD inducer doxorubicin(DOX)to obtain M-CS-AI/DOX.Upon intravenous injection,MCS-AI/DOX was specially recognized and internalized by circulating monocyte in vivo.The formed drugs/monocyte tend to distribute in hypoxia/necrosis region guided by the homing signals released by tumor.Accumulated monocytes then further differentiated into macrophages,up-regulating the expression of legumain and promoting the sensitive-release of chemo-drug DOX,IND,and the mannose-modified CSO(M-CSO).The released IND would specifically regulate immunosuppressive tumor microenvironment,and synergistically inhibit tumor growth with immune activation elements,ICD-induced DOX,and the favorable adjuvant M-CSO.In summary,the self-oriented deep tumor delivery of legumain-cleavable nanovesicles through circulating monocyte makes it possible for reaching tumor regions inaccessible for nanoparticles and provides a novel insight for precise tumor enrichment and immune activation.

SC79 promotes efficient entry of GDNF liposomes into brain parenchyma to repair dopamine neurons through reversible regulation of tight junction proteins

Glial cell line-derived neurotrophic factor(GDNF),a disease-modifying drug for Parkinson’s disease(PD)is in Phase 2 clinical trials(EudraCT number:2011-003866-34),however it is administered by direct intrastriatal delivery via stereotaxy,which is accompanied with intracranial infection,brain tissue damage,and other complications.In addition,because of complex administration routes,clinical trials of GDNF have yielded contrary results,largely due to differences in dose and concentration brought by intracranial device.Herein,a small molecular agonist SC79 was screened to open blood-brain barrier(BBB)and promote GDNF liposomes to get into brain.SC79 reversibly reduces the expression of claudin-5,one of dominant tight junctions of BBB.Animal study showed SC79 promoted liposomes to enter into brain parenchyma 2.43 times more than that of the control.Motor deficits of PD mice receiving SC79 and brain-targeted GDNF liposomes were recovered by 36.70%and tyrosine hydroxylase positive neurons in striatum were restored by 39.90%.Our combination therapy effectively avoids the side effects such as secondary infection and uneven delivery caused by intracranial injection,improving patients’compliance and providing valuable research ideas for the clinic.

Erratum to:SC79 promotes efficient entry of GDNF liposomes into brain parenchyma to repair dopamine neurons through reversible regulation of tight junction proteins

Erratum to Nano Research 2023,16(2):2695-2705 https://doi.org/10.1007/s12274-022-4857-6 The article SC79 promotes efficient entry of GDNF liposomes into brain parenchyma to repair dopamine neurons through reversible regulation of tight junction proteins,written by Xiaomei Wu et al.,was erroneously originally published electronically on the publisher’s internet portal(currently SpringerLink)on 14 September 2022 with Fig.1(f)and a zeta potential value in Section 3.1.

Cell membrane coated-nanoparticles for cancer immunotherapy

Cancer immunotherapy can effectively inhibit cancer progression by activating the autoimmune system, with low toxicity and high effectiveness. Some of cancer immunotherapy had positive effects on clinical cancer treatment. However, cancer immunotherapy is still restricted by cancer heterogeneity, immune cell disability, tumor immunosuppressive microenvironment and systemic immune toxicity. Cell membrane-coated nanoparticles(CMCNs) inherit abundant source cell-relevant functions, including “self” markers, cross-talking with the immune system, biological targeting, and homing to specific regions. These enable them to possess preferred characteristics, including better biological compatibility, weak immunogenicity, immune escaping, a prolonged circulation, and tumor targeting.Therefore, they are applied to precisely deliver drugs and promote the effect of cancer immunotherapy.In the review, we summarize the latest researches of biomimetic CMCNs for cancer immunotherapy,outline the existing specific cancer immune therapies, explore the unique functions and molecular mechanisms of various cell membrane-coated nanoparticles, and analyze the challenges which CMCNs face in clinical translation.

Regulation of pathological BBB restoration via nanostructured ROS-responsive glycolipid-like copolymer entrapping siVEGF for glioblastoma targeted therapeutics

Glioblastoma(GBM)is one of the malignant brain tumors with high mortality and no curative treatments.Abnormally elevated vascular endothelial growth factor(VEGF)in GBM seriously disrupts the blood brain barrier(BBB)with an increased permeability,resulting in poor outcome and prognosis.RNAi interference has shown strong potential to inhibit VEGF expression,thus it is necessary to development an effective and safe gene delivery system possessing the ability to cross the BBB and target GBM cells.This study aims to explore the anti-GBM effect of angiopep-2(Ap)peptide modified reactive oxygen species(ROS)cleavable thioketal(TK)linked glycolipid-like nanocarrier(CSTKSA)delivering anti-VEGF siRNA(R),termed as Ap-CSTKSA/R complexes.Ap functionalized modification produced an enhanced cellular uptake and a stronger bio-distribution of Ap-CSTKSA/R complexes in U87 MG cells and brain tumor tissues,respectively.Ap-CSTKSA/R complexes exhibited great superiority in GBM growth inhibition and finally translated into the longest survival period mainly via receptor-mediated targeting delivery,VEGF gene silencing accompanied with remarkable angiogenesis inhibition,and suppressed expression of caveolin-1 which is involved in BBB functional regulation in the occurrence and treatment of GBM.The study indicated that Ap functionalization on ROS-responsive glycolipid-like copolymer exhibits a promising and effective gene delivery platform for GBM targeted treatment.

Tumor and dendritic cell dual-targeting nanocarriers maximize the therapeutic potential of IDO1 inhibitor in vivo

Researches on indoleamine-2,3-dioxygenase-1(IDO1),a neoplastic pathogenesis-related protein,have provided a new angle of view to regulate malignancy-related immunosuppression.However,the therapeutic efficacy of IDO1 inhibitors is subject to key limitations as both cancer and dendritic cells tend to be trapped in the IDO1-mediated immune dysfunction,which poses challenges to the inhibitory potency of drug regimens in multiple targets.Here,we report on the fabrication technique of a biomimetic nanocarrier that is endowed with the whole array of cancer cell membrane proteins for encapsulating the most used IDO1 probe indoximod(IND).By fully utilizing the homologous adhesion proteins and antigenic motifs on cytomembrane,these nanoparticulate particles are capable of infiltrating tumors and actively accumulating in cancer and dendritic cells,as well as hitching a ride on dendritic cells to tumor-draining lymph nodes.Ultimately,by increasing the distribution of drugs in both tumor cells and dendritic cells in tumor-draining lymph nodes,these formulations greatly enhance the efficacy of IND without the aid of chemotherapeutic drugs,achieving substantial control of tumor growth.Overall,this leverage of bionanotechnology maximizes the therapeutic potential of IND and can provide a theoretical reference for the clinical application of IDO1 inhibitors.

Erratum to: Inhibition of chemotherapy-related breast tumor EMT by application of redox-sensitive siRNA delivery system CSO-ss-SA/siRNA along with doxorubicin treatment

The original version of this article(Liu et al.,2020)unfortunately contained some mistakes.1.Figs.7c and 7d in p.229 were incorrect.The upper left and bottom left pictures in Fig.7c were accidentally duplicated with the pictures at the same position of Fig.la.The upper right and bottom right pictures were mistakenly placed in Fig.