Identification and characterization of immune-related microRNAs in hybrid snakehead(Channa maculata♀ × Channa argus♂)after treated by Echinacea purpurea (Linn.) Moench.

Echinacea purpurea (Linn.) Moench (EP) is a globally popular herbal medicine, which showed effects on growth promotion, antioxidant and immunomodulatory activities in fish culture world widely. However, there are few studies about the effects on miRNAs by EP in fish. The hybrid snakehead fish (Channa maculate♀ × Channa argus ♂) was new important economic specie of freshwater aquaculture in China with high market value and demand while there were only a few reports about its miRNAs. To overview immune-related miRNAs of the hybrid snakehead fish and to further understand the immune regulating mechanism of EP, we herein constructed and analyzed three small RNA libraries of immune tissues including liver, spleen and head kidney of the fish with or without EP treatment via Illumina high-throughput sequencing technology. Results showed that EP can affect the immune activities of fish by the miRNA-regulated ways. Totally, 67 (47 up and 20 down) miRNAs in liver, 138 (55 up and 83 down) miRNAs in spleen, and 251 (15 up and 236 down) miRNAs in spleen were detected, as well as 30, 60, 139 kinds of immune-related miRNAs belonging to 22, 35 and 66 families of the three tissues respectively. The expressions of 8 immune-related miRNA family members were found in all the three tissues, including miR-10, miR-133, miR-22 and etc. Some miRNAs have been identified involved in the innate and adaptive immune responses, such as the miR-125, miR-138, and miR-181 family. Ten miRNA families with antioxidant target genes were also discovered, including miR-125, miR-1306, and miR-138, etc. Results from Gene Ontology (GO) and KEGG pathway analysis further confirmed there are a majority immune response targets of the miRNAs involved in the EP treatment process. Our study deepened understanding roles of miRNAs in fish immune system and provides new ideas for the study of immune mechanism of EP.

Vitamin E performs antioxidant effect via PAP retrograde signaling pathway in Nile tilapia (Oreochromis niloticus).

PAP (3'-phosphoadenosine 5'-phosphate) is a ubiquitous phosphoric acid and a natural inhibitor of the XRN (5'-3'exoribonuclease) family. It was proved to enter the nucleus through the retrograde signaling pathway and inhibit XRN2 to prevent the degradation of miRNA precursors, thus promoting the anti-oxidation miRNA level in Arabidopsis thaliana. Vitamin E (tocopherol) was proved to promote the accumulation of PAP in the plant, which facilitates PAP into the nucleus to accomplish its antioxidant function. However, the relationship between VE and PAP in animals is unclear. To identify the relationship between VE and PAP and to uncover the function of PAP in fish, we investigated the performance of VE and PAP in Nile tilapia by comparing the antioxidant indicators (SOD, GSH-Px, and CAT), the Keap1-Nrf2 signaling pathway, and the miRNA expression profiles. Results showed that the antioxidant effect of VE and PAP showed similar character either in tilapia liver or in serum: the activities of GSH-Px and CAT of both groups were significantly increased (P < 0.05); the SOD activity of the VE group was significantly increased (P < 0.05), and although the result of the PAP group was not so significant (P > 0.05), PAP improved the SOD level, too. The two groups also showed similar character in the tilapia liver; both did not significantly increase the liver δ-VE content (P > 0.05). However, VE significantly increased the content of α-VE and γ-VE (P < 0.05), while the PAP group was insignificant (P > 0.05). Feed with VE and intraperitoneal injection of PAPs reagent both increased the PAP content in the liver of tilapia, and the effect of the VE group was more significant (P < 0.05) than that of the PAP group (P > 0.05). Both groups reduced the expression of Keap1 and Cullin3 genes and improved the level of HO-1 gene expression, with the improved miRNA level of Nrf2. As a logical result, they decreased the expression of XRN1 and XRN2. By profile sequencing, we further identified some antioxidant closely related miRNAs shared in the VE and PAP groups, including miR-30, miR-24, miR-19b, and miR-100. By comparing the regulating mechanism of VE and PAP of feed supply and intraperitoneal injection, we proved that VE and PAP were closely related in fish; VE promoted the gathering of PAP. The latter retrograded into the nucleus of the fish liver to inhibit the expression of XRN genes and to up-regulate antioxidant miRNA levels as it does in plants. Only the PAP can accomplish the antioxidant activities, while VE promotes the process. Our study laid the foundation for the application of PAP as a new antioxidant agent in fish farming and benefit a further understanding of the VE antioxidant function in fish.

Tailored Chemodynamic Nanomedicine Improves Pancreatic Cancer Treatment via Controllable Damaging Neoplastic Cells and Reprogramming Tumor Microenvironment.

Pancreatic ductal adenocarcinoma (PDAC) strongly resists standard therapies since KRAS-mutated cancer cells harbor endogenous resistance toward chemotherapy-induced apoptosis and tumor-associated macrophages (TAMs) activate stroma cells to create the nearly impenetrable matrix. Herein, we developed a tailored nanocomplex through the self-assembly of synthetic 4-(phosphonooxy)phenyl-2,4-dinitrobenzenesulfonate and Fe3+ followed by hyaluronic acid decoration, realizing chemodynamic therapy (CDT) to combat PDAC. By controllably releasing its components in a GSH-sensitive manner under the distinctive redox homeostasis in cancer cells and TAMs, the nanocomplex selectively triggered a Fenton reaction to induce oxidative damage in cancer cells and simultaneously repolarized TAMs to deactivate stromal cells and thus attenuate stroma. Compared to gemcitabine, CDT remarkably inhibited tumor growth and prolonged animal survival in orthotopic PDAC models without noticeable side effects. This study provides a promising strategy to improve the treatment of PDAC through CDT-mediated controlled cancer cells damage and reprogramming of the stromal microenvironment.

Development of a Lateral Flow Strip-Based Recombinase Polymerase Amplification Assay for the Detection of Haemonchus contortus in Goat Feces.

Haemonchosis remains a significant problem in small ruminants. In this study, the assay of recombinase polymerase amplification (RPA) combined with the lateral flow strip (LFS-RPA) was established for the rapid detection of Haemonchus contortus in goat feces. The assay used primers and a probe targeting a specific sequence in the ITS-2 gene. We compared the performance of the LFS-RPA assay to a PCR assay. The LFS-RPA had a detection limit of 10 fg DNA, which was 10 times less compared to the lowest detection limit obtained by PCR. Out of 24 goat fecal samples, LFS-RPA assay detected H. contortus DNA with 95.8% sensitivity, compared to PCR, 79.1% sensitivity. LFS-RPA assay did not detect DNA from other related helminth species and demonstrated an adequate tolerance to inhibitors present in the goat feces. Taken together, our results suggest that LFS-RPA assay had a high diagnostic accuracy for the rapid detection of H. contortus and merits further evaluation.

MicroRNAs and Related Cytokine Factors Quickly Respond in the Immune Response of Channel Catfish to Lipopolysaccharides and ß-Glucan Stimulation.

MicroRNAs (miRNAs) are well-known as powerful regulators of gene expression, with their potential to serve for immunology widely researched in mammals and birds but rarely in fishes. To better understand fish immunology behavior, we herein investigated nine immune-related miRNAs that were reported in other animals, as well as five related cytokine factors and lysozyme (LZM) in the liver, anterior kidney, and spleen of Channel Catfish Ictalurus punctatus after being stimulated by lipopolysaccharides (LPS) and ß-glucan. We also predicated the potential targets of these miRNAs via bioinformatics and further investigated nine of them via quantitative real-time PCR. Results showed that expressions of the nine miRNAs were quickly changed in varying extent after stimulation by LPS, especially for miR-122, miR-142a, miR-155, and miR-223, which were significantly changed in spleen, and the same occurred for the LZM and three cytokine factors TNF-α, IFN-γ and TLR2. Compared with LPS, although most of the miRNAs and the cytokine genes were also affected by ß-glucan, the extent of the effect was weak. Bioinformatics analysis revealed many immune-related targets of the miRNAs, with some of them reported by previous studies. For the nine investigated target genes, seven targets (77.8%) were significantly upregulated after the stimulation of LPS. It therefore can be inferred that the immune-related miRNAs, LZM, and cytokine factors elicited quick immune responses of Channel Catfish to LPS stimulation as in other animals, but the regulation mechanism of miRNAs might be complex and diverse. This research will contribute to a better understanding will support further immunology research in fishes.

The miR-155 regulates cytokines expression by SOSC1 signal pathways of fish in vitro and in vivo.

MiR-155 is reported as immune regulated miRNA in mammalian corresponding to immunity, antibacterial and antiviral effects regulation. However, the roles and mechanisms of the miRNA have remained largely undefined. We herein comprehensively investigated the functions of miR-155 in vitro and in vivo by miR-155 mimics, agomir and antagomir in Cyprinus carpio and Ictalurus punctatus, with the target genes in the SOSC1 pathway certified in I. punctatus via luciferase reporter assays. Results showed that the miR-155 regulated the expressions of cytokines, including TNF-α, IFN-γ, IL-1ß, IL-6 and IL-10. Further research confirmed SOSC1 as one of the targets of the miRNA, and the JAK1/STAT3/SOSC1 signal pathway involved in the miR-155 effects on the expression of immune cytokines as well. Additionally, the changes of TLR2 in fish may also be related to miR-155 along with its target SOCS1, and the TLR2/MyD88 pathway may partly participate in the effects of the miR-155 on the cytokines. The research here confirmed that the miR-155 can regulate cytokines expression by SOSC1 signal pathways of fish in vitro and in vivo, which would provide resources for understanding and studying about immune regulation in fish.

Exercise and Organ Cross Talk.

Chronic heart failure, diabetes, depression, and other chronic diseases are associated with high mortality rate and low cure rate. Exercise induces muscle contraction and secretes multiple myokines, which affects the signaling pathways in skeletal muscle tissues and regulate remote organ functions. Exercise is known to be effective in treating a variety of chronic diseases. Here we summarize how exercise influences skeletal muscle, heart, brain, gut, and liver, and prevents heart failure, cognitive dysfunction, obesity, fatty liver, and other diseases. Exercise training may achieve additional benefits as compared to the present medication for these chronic diseases through cross talk among skeletal muscle and other organs.

Metformin and Docosahexaenoic Acid Hybrid Micelles for Premetastatic Niche Modulation and Tumor Metastasis Suppression.

Metastasis is the major cause of high mortality in cancer patients; thus, blocking the metastatic process is of critical importance for cancer treatments. The premetastatic niche, a specialized microenvironment with aberrant changes related to inflammation, allows the colonization of circulating tumor cells (CTCs) and serves as a potential target for metastasis prevention. However, little effort has been dedicated to developing nanomedicine to amend the premetastatic niche. Here this study reports a premetastatic niche-targeting micelle for the modulation of premetastatic microenvironments and suppression of tumor metastasis. The micelles are self-assembled with the oleate carbon chain derivative of metformin and docosahexaenoic acid, two anti-inflammatory agents with low toxicity, and coated with fucoidan for premetastatic niche-targeting. The obtained functionalized micelles (FucOMDs) exhibit an excellent blood circulation profile and premetastatic site-targeting efficiency, inhibit CTC adhesion to activated endothelial cells, alleviate lung vascular permeability, and reverse the aberrant expression of key marker proteins in premetastatic niches. As a result, FucOMDs prevent metastasis formation and efficiently suppress both primary-tumor growth and metastasis formation when combined with targeted chemotherapy. Collectively, the findings here provide proof of concept that the modulation of the premetastatic niche with targeted anti-inflammatory agents provides a potent platform and a safe and clinical translational option for the suppression of tumor metastasis.

Sequential Targeting TGF-ß Signaling and KRAS Mutation Increases Therapeutic Efficacy in Pancreatic Cancer.

Pancreatic cancer is a highly aggressive malignancy that strongly resists extant treatments. The failure of existing therapies is majorly attributed to the tough tumor microenvironment (TME) limiting drug access and the undruggable targets of tumor cells. The formation of suppressive TME is regulated by transforming growth factor beta (TGF-ß) signaling, while the poor response and short survival of almost 90% of pancreatic cancer patients results from the oncogenic KRAS mutation. Hence, simultaneously targeting both the TGF-ß and KRAS pathways might dismantle the obstacles of pancreatic cancer therapy. Here, a novel sequential-targeting strategy is developed, in which antifibrotic fraxinellone-loaded CGKRK-modified nanoparticles (Frax-NP-CGKRK) are constructed to regulate TGF-ß signaling and siRNA-loaded lipid-coated calcium phosphate (LCP) biomimetic nanoparticles (siKras-LCP-ApoE3) are applied to interfere with the oncogenic KRAS. Frax-NP-CGKRK successfully targets the tumor sites through the recognition of overexpressed heparan sulfate proteoglycan, reverses the activated cancer-associated fibroblasts (CAFs), attenuates the dense stroma barrier, and enhances tumor blood perfusion. Afterward, siKras-LCP-ApoE3 is efficiently internalized by the tumor cells through macropinocytosis and specifically silencing KRAS mutation. Compared with gemcitabine, this sequential-targeting strategy significantly elongates the lifespans of pancreatic tumor-bearing animals, hence providing a promising approach for pancreatic cancer therapy.

Branched-chain amino acid (BCAA) supplementation enhances adaptability to exercise training of mice with a muscle-specific defect in the control of BCAA catabolism.

Branched-chain α-keto acid dehydrogenase (BCKDH) kinase (BDK) suppresses the branched-chain amino acid (BCAA) catabolism by inactivation of the BCKDH complex. The muscle-specific BDK-deficient (BDK-mKO) mice showed accelerated BCAA oxidation in muscle and decreased endurance capacity after training (Xu et al. PLoS One. 12 (2017) e0180989). We here report that BCAA supplementation overcompensated endurance capacity in BDK-mKO mice after training.

Transcriptional changes of mouse splenocyte organelle components following acute infection with Toxoplasma gondii.

Toxoplasmosis is a globally spread zoonosis. The pathogen Toxoplasma gondii can hijack cellular organelles of host for replication. Although a number of important cellular life events are controlled by cell organelles, very little is known of the transcriptional changes of host cellular organelles after infection with T. gondii. Herein, we performed RNA-sequencing (RNA-seq) and bioinformatics analyses to study the global organelle component changes. It was found that many transcripts of the mouse spleen cellular organelle components were altered by acute T. gondii infection with the RH strain (Type I). Most differentially expressed transcripts of mitochondrial components were downregulated, especially those involved in biosynthetic and metabolic processes. Moreover, mitochondria based apoptosis process was downregulated. In terms of cytoskeleton, most differentially expressed transcript of cytoskeleton components were also downregulated, including septin cytoskeleton, cytoskeleton organization, centrosome and myosin. For endolysosomal system, ion transporters were downregulated at mRNA level, whereas the cytolytic components were increased, such as granzymes, Rab27a and perforin1 (Prf1). The main transcripts of Golgi apparatus components involved in sialylation or vesicle-mediated transportation were downregulated, while immune related components were upregulated. For endoplasmic reticulum (ER), posttranslational modification, drug metabolism and material transportation related transcripts were downregulated. In addition, T. gondii antigen cross-presentation by MHC-I complex could be downregulated by the downregulation of CD76 and ubiquitination related transcripts. The present study, for the first time, described the transcriptional changes of the mouse spleen cellular organelles following acute T. gondii infection, which provides a foundation to study the interaction between T. gondii and host cells at the sub-cellular level.

Recombinase polymerase amplification (RPA) combined with lateral flow (LF) strip for equipment-free detection of Cryptosporidium spp. oocysts in dairy cattle feces.

Cryptosporidium is a widespread protozoan parasite that infects a large number of vertebrate animals, resulting in varying degrees of diarrhea or even death. As dairy cattle feces is an important source of Cryptosporidium spp. infection, development of a handy and accurate detection method via its oocysts in dairy cattle feces would be interesting and necessary. We herein developed a quick detecting method using recombinase polymerase amplification (RPA) combined with lateral flow (LF) strip to detect DNA of Cryptosporidium oocysts in dairy cattle feces. The DNA was released by boiled water with 0.1 % N-lauroylsarcosine sodium salt (LSS). The established method was proven to be of higher sensitivity than normal polymerase chain reaction (PCR) amplification with the lowest detection of 0.5 oocyst per reaction, and specificity with no cross reactivity to other common protozoan species in the intestine of dairy cattle. The diagnostic method established herein is simple, rapid, and cost-effective, and has potential for further development as a diagnostic kit for the diagnosis of cryptosporidiosis of dairy cattle.

Regulation of the plasma amino acid profile by leucine via the system L amino acid transporter.

Plasma concentrations of amino acids reflect the intracellular amino acid pool in mammals. However, the regulatory mechanism requires clarification. In this study, we examined the effect of leucine administration on plasma amino acid profiles in mice with and without the treatment of 2-aminobicyclo-(2,2,1)-heptane-2-carboxylic acid (BCH) or rapamycin as an inhibitor of system L or mammalian target of rapamycin complex 1, respectively. The elevation of plasma leucine concentration after leucine administration was associated with a significant decrease in the plasma concentrations of isoleucine, valine, methionine, phenylalanine, and tyrosine; BCH treatment almost completely blocked the leucine-induced decrease in plasma amino acid concentrations. Rapamycin treatment had much less effects on the actions of leucine than BCH treatment. These results suggest that leucine regulates the plasma concentrations of branched-chain amino acids, methionine, phenylalanine, and tyrosine, and that system L amino acid transporters are involved in the leucine action.

Prevalence of Toxoplasma gondii in Dogs in Zhanjiang, Southern China.

Toxoplasmosis, caused by Toxoplasma gondii, is a parasitic zoonosis with worldwide distribution. The present study investigated the prevalence of T. gondii in dogs in Zhanjiang city, southern China, using both serological and molecular detection. A total of 364 serum samples and 432 liver tissue samples were collected from the slaughter house between December 2012 and January 2013 and were examined for T. gondii IgG antibody by ELISA and T. gondii DNA by semi-nested PCR based on B1 gene, respectively. The overall seroprevalence of T. gondii IgG antibody was 51.9%, and T. gondii DNA was detected in 37 of 432 (8.6%) liver tissue samples. These positive DNA samples were analyzed by PCR-RFLP at 3'- and 5'-SAG2. Only 8 samples gave the PCR-RFLP data, and they were all classified as type I, which may suggest that the T. gondii isolates from dogs in Zhanjiang city may represent type I or type I variant. This study revealed the high prevalence of T. gondii infection in dogs in Zhanjiang city, southern China. Integrated measures should be taken to prevent and control toxoplasmosis in dogs in this area for public health concern.

[Research Progress and Application Future of MicroRNA-36].

MicroRNA-36 (miR-36) is a recently discovered miRNA family which including at least eight members, and specifically existed in helminths compared with other miRNAs that widely exists in almost all kinds of lives. This paper reviews recent research advances about miR-36 to provide further fundamental information for helminth and miRNA study.

Comparative proteomic analysis of different Toxoplasma gondii genotypes by two-dimensional fluorescence difference gel electrophoresis combined with mass spectrometry.

Toxoplasma gondii is a protozoan parasite infecting almost all warm-blooded animals and humans. There are three infective stages of T. gondii: the tachyzoites, the bradyzoites, and the oocysts. The tachyzoite is a rapidly multiplying stage and the main pathogenic factor. In North America and Europe, T. gondii is consisted of four major clonal lineages (namely Types I, II, III, and Type 12). In this study, we explored the proteomic profiles of different genotypes (Type I-RH strain, Type II-PRU strain, Type II-TgQHO strain, and ToxoDB 9-TgC7 strain) of T. gondii tachyzoites by using 2D DIGE combined with MALDI-TOF MS. Totally, 110 differentially abundant protein spots were selected. Of these, 98 spots corresponding to 56 proteins from T. gondii were successfully identified. These included surface antigen (SAG1), heat shock protein 70 (Hsp 70), disulfide isomerase, coronin, heat shock protein 60 (Hsp 60), pyruvate kinase, receptor for activated C kinase 1, and peroxiredoxin. Gene ontology enrichment analysis revealed that most of the differentially abundant proteins were involved in biological regulation, metabolic process, response to stress, binding, antioxidant activity, and transporter activity. According to the KEGG metabolic pathway maps of T. gondii, some identified proteins were involved in the glycolytic/gluconeogenesis pathway. The present study identified differentially abundant proteins among different genotypes of T. gondii and these findings have implications for the better understanding of the phenotypic differences among the examined T. gondii genotypes, which in turn may contribute to the better control of toxoplasmosis.

Enhancement of neighbouring-group participation in Cu0-promoted cross-coupling gem-difluoromethylenation of aryl/alkenyl halides with 1,3-azolic difluoromethyl bromides.

A copper(0)-promoted direct reductive gem-difluoromethylenation of unactivated aryl or alkenyl halides with benzo-1,3-azolic (oxa-, thia- or aza-) difluoromethyl bromides or 2-bromodifluoromethyl-1,3-oxazoline has been developed for the construction of pharmaceutically important gem-difluoromethylene-linked twin molecules. The unique π-conjugated aryl-fused 1,3-azolic moiety in difluoromethyl bromide substrates could stabilise the reaction intermediates, which promotes the reactivities, providing facile access to the cross-coupling products in good to excellent yields, and allowing significant functional group tolerance. The reaction exhibits an enhanced neighbouring-group-participation effect. This method could provide a new strategy for the construction of gem-difluoromethylene-linked identical or nonidentical twin drugs through further functionalisation of 1,3-azolic skeletons.

Comparative analysis of microRNA profiles between adult Ascaris lumbricoides and Ascaris suum.

BACKGROUND: The parasitic nematodes Ascaris lumbricoides and A. suum are of great public health and economic significance, and the two taxa were proposed to represent a single species. miRNAs are known with functions of gene regulations at post-transcriptional level. RESULTS: We herein compared the miRNA profiles of A. lumbricoides and A. suum female adults by Solexa deep sequencing combined with bioinformatics analysis and stem-loop real-time PCR. Using the A. suum genome as the reference genome, we obtained 171 and 494 miRNA candidates from A. lumbricoides and A. suum, respectively. Among which, 74 miRNAs were shared between the two taxa, 97 and 420 miRNAs were A. lumbricoides and A. suum specific. Target and function prediction revealed a significant set of targets which are related to ovarian message protein, vitellogenin and chondroitin proteoglycan of the two nematodes. Enrichment analysis revealed that the percentages of most predicted functions of the miRNA targets were similar, with some taxon specific or taxon enhanced functions, such as different target numbers, specific functions (NADH dehydrogenase and electron carrier functions), etc. CONCLUSIONS: This study characterized comparatively the miRNAs of adult A. lumbricoides and A. suum, and the findings provide additional evidence that A. lumbricoides and A. suum represent a single species. Due to the fast evolution nature of miRNAs and the different parasitic living conditions of humans and pigs, the phenomenon above might indicate a fast evolution of miRNAs of Ascaris in humans and pigs.

Precise Modulation of Pericyte Dysfunction by a Multifunctional Nanoprodrug to Ameliorate Alzheimer's Disease.

Pericyte dysfunction severely undermines cerebrovascular integrity and exacerbates neurodegeneration in Alzheimer's disease (AD). However, pericyte-targeted therapy is a yet-untapped frontier for AD. Inspired by the elevation of vascular cell adhesion molecule-1 (VCAM-1) and reactive oxygen species (ROS) levels in pericyte lesions, we fabricated a multifunctional nanoprodrug by conjugating the hybrid peptide VLC, a fusion of the VCAM-1 high-affinity peptide VHS and the neuroprotective apolipoprotein mimetic peptide COG1410, to curcumin (Cur) through phenylboronic ester bond (VLC@Cur-NPs) to alleviate complex pericyte-related pathological changes. Importantly, VLC@Cur-NPs effectively homed to pericyte lesions via VLC and released their contents upon ROS stimulation to maximize their regulatory effects. Consequently, VLC@Cur-NPs markedly increased pericyte regeneration to form a positive feedback loop and thus improved neurovascular function and ultimately alleviated memory defects in APP/PS1 transgenic mice. We present a promising therapeutic strategy for AD that can precisely modulate pericytes and has the potential to treat other cerebrovascular diseases.

Multidimensional autophagy nano-regulator boosts Alzheimer's disease treatment by improving both extra/intraneuronal homeostasis.

Intraneuronal dysproteostasis and extraneuronal microenvironmental abnormalities in Alzheimer's disease (AD) collectively culminate in neuronal deterioration. In the context of AD, autophagy dysfunction, a multi-link obstacle involving autophagy downregulation and lysosome defects in neurons/microglia is highly implicated in intra/extraneuronal pathological processes. Therefore, multidimensional autophagy regulation strategies co-manipulating "autophagy induction" and "lysosome degradation" in dual targets (neuron and microglia) are more reliable for AD treatment. Accordingly, we designed an RP-1 peptide-modified reactive oxygen species (ROS)-responsive micelles (RT-NM) loading rapamycin or gypenoside XVII. Guided by RP-1 peptide, the ligand of receptor for advanced glycation end products (RAGE), RT-NM efficiently targeted neurons and microglia in AD-affected region. This nano-combination therapy activated the whole autophagy-lysosome pathway by autophagy induction (rapamycin) and lysosome improvement (gypenoside XVII), thus enhancing autophagic degradation of neurotoxic aggregates and inflammasomes, and promoting Aß phagocytosis. Resultantly, it decreased aberrant protein burden, alleviated neuroinflammation, and eventually ameliorated memory defects in 3 × Tg-AD transgenic mice. Our research developed a multidimensional autophagy nano-regulator to boost the efficacy of autophagy-centered AD therapy.