Polypeptide Sequence Research Articles

A new approach for purification of the catalytic site of the angiotensin-conversion enzyme, N-domain, mediated by the ELP-Intein system

Angiotensin-converting enzyme I (ACE) is a key part of the renin-angiotensin system. Its main function is to regulate blood pressure and the balance of salts in the body. Somatic ACE has two domains, N-C-, each of which has a catalytic site that exhibits 60%sequence identity. The N-domain has a specific action in the hydrolysis of beta-amyloid bodies and angiotensin (1–7), which activates the MAS receptor and triggers anti-thrombotic and anti-inflammatory actions. Our goal was to obtain the catalytic site Ala361 to Gly468 of the N domain region, csACEN, without needing purification by chromatography. We employed a method that uses an Elastin-like Polypeptide (ELP) and Intein sequences linked to the peptide of interest. The more differential for obtaining the pure peptide was the cultivation temperatures in the synthesis of ELPcsACEN at 37 °C, with a significant increase in expression. In the purification by ELP precipitation, we recorded the highest efficiency in the concentrations of 0.57 M and 0.8 M of ammonium sulfate buffer. Intein autocleavage study allows removal of the ELP sequence at acidic pH, with the buffers MES and Tris-HCl The present study defined the best conditions for obtaining pure csACEN that the literature has not yet described for peptides. Obtaining pure csACEN aims at future studies for therapeutic use in hypertension, Alzheimer's, and oncology.

Antiangiogenic potential of small polypeptide sequences: In vivo assays, cytotoxicity, synthetic approaches and influence of C-terminal carboxyamidation

The search for new inhibitors of tyrosine kinase receptors involved in angiogenesis is a frequent topic in the design of antiangiogenic drugs. Michaloski and coworkers have obtained the peptide sequences PCAIWF-OH and PSAIWF-OH that showed potential inhibition of VEGF receptors. The present work describes the obtention of these peptides and their carboxyamidated analogues, which are prepared by a more efficient method. Their antiangiogenic activities were evaluated in vivo using the chicken embryo chorioallantoic membrane model. Assays with ARPE-19 cells were carried out to evaluate toxicity. PSAIWF-NH2 showed the higher inhibition of angiogenesis, at levels comparable to the bevacizumab. This carboxyamidated analogue carrying a serine has the advantage of not undergoing dimerization and it can be obtained by a more efficient and cheaper synthetic method. Retinal cells displayed in general high cell viability in the presence of the four peptides. PSAIWF-NH2 presented the highest angiogenic inhibition and the lowest toxicity. To evaluate the feasibility of prolonged and controlled release, PSAIWF-NH2 was incorporated into PLGA implants. The delivery profile was characterized by two phases, initially marked by a burst of release, followed by the sustained release of lower quantities during 36 days. Peptide concentrations were kept at levels that showed angiogenic inhibition.

Combining High-Pressure NMR and Geometrical Sampling to Obtain a Full Topological Description of Protein Folding Landscapes: Application to the Folding of Two MAX Effectors from Magnaporthe oryzae.

Despite advances in experimental and computational methods, the mechanisms by which an unstructured polypeptide chain regains its unique three-dimensional structure remains one of the main puzzling questions in biology. Single-molecule techniques, ultra-fast perturbation and detection approaches and improvement in all-atom and coarse-grained simulation methods have greatly deepened our understanding of protein folding and the effects of environmental factors on folding landscape. However, a major challenge remains the detailed characterization of the protein folding landscape. Here, we used high hydrostatic pressure 2D NMR spectroscopy to obtain high-resolution experimental structural information in a site-specific manner across the polypeptide sequence and along the folding reaction coordinate. We used this residue-specific information to constrain Cyana3 calculations, in order to obtain a topological description of the entire folding landscape. This approach was used to describe the conformers populating the folding landscape of two small globular proteins, AVR-Pia and AVR-Pib, that belong to the structurally conserved but sequence-unrelated MAX effectors superfamily. Comparing the two folding landscapes, we found that, in spite of their divergent sequences, the folding pathway of these two proteins involves a similar, inescapable, folding intermediate, even if, statistically, the routes used are different.

Salt- and pH-Dependent Thermal Stability of Photocomplexes from Extremophilic Bacteriochlorophyll b-Containing Halorhodospira Species.

Halorhodospira (Hlr.) species are the most halophilic and alkaliphilic of all purple bacteria. Hlr. halochloris exhibits the lowest LH1 Qy transition energy among phototrophic organisms and is the only known triply extremophilic anoxygenic phototroph, displaying a thermophilic, halophilic, and alkaliphilic phenotype. Recently, we reported that electrostatic charges are responsible for the unusual spectroscopic properties of the Hlr. halochloris LH1 complex. In the present work, we examined the effects of salt and pH on the spectroscopic properties and thermal stability of LH1-RCs from Hlr. halochloris compared with its mesophilic counterpart, Hlr. abdelmalekii. Experiments in which the photocomplexes were subjected to different levels of salt or variable pH revealed that the thermal stability of LH1-RCs from both species was largely retained in the presence of high salt concentrations and/or at alkaline pH but was markedly reduced by lowering the salt concentration and/or pH. Based on the amino acid sequences of LH1 polypeptides and their composition of acidic/basic residues and the Hofmeister series for cation/anion species, we discuss the importance of electrostatic charge in stabilizing the Hlr. halochloris LH1-RC complex to allow it to perform photosynthesis in its warm, hypersaline, and alkaline habitat.

Improved stability and pharmacokinetics of wogonin through loading into PASylated ferritin

Wogonin (Wog) plays an important role in human diseases, especially cancer and inflammatory diseases, but its poor solubility, unstable metabolism and low bioavailability greatly limit its application in biomedical fields. Therefore, we developed a temperature-dependent method to encapsulate wogonin into a novel ferritin-based nanocarrier. To improve the loading capacity and stability, the human H chain ferritin (HFtn) was functionalized with a repetitive polypeptide sequence composed of proline (Pro), alanine (Ala), and serine (Ser) in different residues lengths (PAS10 and PAS30). Wogonin loading and release studies demonstrated that the encapsulation efficiency and stability of the PASylated nanocarriers were significantly higher than those of the wild type. PAS-HFtn-Wog exhibited enhanced cytotoxicity to MCF-7 breast cancer cells and HepG2 liver cancer cells. Notably, the PASylated HFtn, especially PAS30-HFtn greatly prolonged the pharmacokinetics of wogonin in the mice bloodstream. Therefore, wogonin-loaded PAS-HFtn may be a promising drug candidate for cancer therapy.

Spatial covariance analysis reveals the residue-by-residue thermodynamic contribution of variation to the CFTR fold

Although the impact of genome variation on the thermodynamic properties of function on the protein fold has been studied in vitro, it remains a challenge to assign these relationships across the entire polypeptide sequence in vivo. Using the Gaussian process regression based principle of Spatial CoVariance, we globally assign on a residue-by-residue basis the biological thermodynamic properties that contribute to the functional fold of CFTR in the cell. We demonstrate the existence of a thermodynamically sensitive region of the CFTR fold involving the interface between NBD1 and ICL4 that contributes to its export from endoplasmic reticulum. At the cell surface a new set of residues contribute uniquely to the management of channel function. These results support a general ‘quality assurance’ view of global protein fold management as an SCV principle describing the differential pre- and post-ER residue interactions contributing to compartmentalization of the energetics of the protein fold for function. Our results set the stage for future analyses of the quality systems managing protein sequence-to-function-to-structure broadly encompassing genome design leading to protein function in complex cellular relationships responsible for diversity and fitness in biology in response to the environment.

Identification and characterization of MKK6 and AP-1 in Anodonta woodiana reveal their potential roles in the host defense response against bacterial challenge

Mitogen-activated protein kinase kinase 6 (MKK6) and activator protein-1 (AP-1) are two of the essential regulatory proteins in the p38 mitogen-activated protein kinase (MAPK) pathway, which participates in the innate immune response to bacterial infections. In this study, molluscan MKK6 (AwMKK6) and AP-1 (AwAP-1) genes were cloned and identified from Anodonta woodiana. The open reading frame (ORF) of AwMKK6 encodes for a putative polypeptide sequence of 345 amino acids containing a conserved serine/threonine protein kinase (S_TKc) domain, a SVAKT motif and a DVD domain. AwAP-1 consists of 294 amino acids including a typical nuclear localization signal (NLS), a Jun domain and a basic region leucine zipper (BRLZ) domain. Quantitative real-time PCR analysis showed that both AwMKK6 and AwAP-1 were widely expressed in all selected tissues of A. woodiana and their transcript levels in hemocytes were significantly upregulated when challenged with Aeromonas hydrophila and lipopolysaccharide (LPS). Additionally, the signaling molecules of the AwMKK6/AwAP-1 pathway including AwTLR4, AwMyD88, AwTRAF6, AwMEKK1, AwMEKK4, AwASK1, AwTAK1 and Awp38 mRNA expression showed a stronger responsiveness to LPS challenge in hemocytes of A. woodiana. RNA interference (RNAi) experiments indicated that the silencing of AwMKK6 or AwAP-1 could decrease the mRNA expression levels of immune effectors (AwTNF, AwLYZ and AwDefense). Subcellular localization studies suggested that AwMKK6 and AwAP-1 were distributed throughout the cells and nucleus, respectively, and their overexpression could significantly enhance the transcriptional activities of AP-1-Luc in HEK293T cells. These findings suggest that MKK6 and AP-1 play a major role in the host defense response to bacterial injection, which may make contributions to a better understanding of the immune function of the p38 MAPK pathway in mollusks.

Reviewing findings on the polypeptide sequence of the SARS-CoV-2 S-protein to discuss the origins of the virus.

Several investigations suggested origins of SARS-CoV-2 from the recombination of coronaviruses of various animals, including the bat Rhinolophus affinis and the pangolin Manis javanica, despite the processes describing the adaptation from a reservoir of animals to human are still debated. In this perspective, I will remark two main inconsistencies on the origins of SARS-CoV-2: polypeptide sequence alignment of the S-proteins does not return the expected identity of the receptor-binding motif among most of pangolin-CoVs and SARS-CoV-2; accurate referencing for samplings and sequencing deposition of the ancestral bat coronavirus named RaTG13 was missing since the first reports on the SARS-CoV-2 coronavirus. This contribution aims to stimulate discussion about the origins of SARS-CoV-2 and considers other intermediate hosts as a reservoir for coronavirus.

Spironolactone alleviates myocardial fibrosis via inhibition of Ets-1 in mice with experimental autoimmune myocarditis.

Spironolactone improves cardiac structure, function and prognosis in patients with heart failure and delays the progression of cardiac fibrosis. However, the exact underlying mechanism of this process remains to be elucidated. The present study therefore aimed to explore the protective effect and underlying mechanism of the aldosterone receptor antagonist, spironolactone, on myocardial fibrosis in mice with experimental autoimmune myocarditis (EAM). The EAM model was induced in BALB/c mice via immunization with murine cardiac α-myosin heavy chain sequence polypeptides. The cardiac function of the mice was assessed using echocardiography and the levels of inflammatory cytokines were quantified using ELISA. E26 transformation-specific sequence-1 (Ets-1) expression was knocked down using lentivirus-mediated small interference RNA. Total collagen deposition was assessed using Masson's trichrome and Ets-1, TGF-β1, Smad2/3, collagen I and III protein expression levels were detected using immunohistochemistry and western blotting. MMP-2 and MMP-9 mRNA expression levels and activity was determined using reverse transcription-quantitative PCR and gelatin zymography, respectively. The results of the present study demonstrated that spironolactone significantly improved myocardium hypertrophy, diastolic cardiac function and decreased myocardial inflammation and collagen deposition induced by EAM. Spironolactone treatment significantly inhibited Ets-1 and smad2/3 phosphorylation. In addition, inhibition of Ets-1 reduced the expression and activity of MMP-2 and MMP-9 and decreased cardiac fibrosis in EAM mice. The results indicated that the improvement of myocardial fibrosis by spironolactone may be associated with the TGF-β1/Smad-2/3/Ets-1 signaling pathway in EAM mice.

Evaluation of RevX solution extract as a potential inhibitor of the main protease of SARS-CoV-2—In vitro study and molecular docking

The main protease (Mpro) of SARS-CoV-2 is a protease necessary for viral polyprotein processing and maturation. Mpro cleaves the polypeptide sequence after the glutamine residues. There is no known cellular protease with this substrate specificity in humans; therefore, it is considered an attractive drug target. Previously, fermented sorghum extract RevX (trademark of Revolutrx INC.) solution significantly alleviated physical decline and complications in a patient with lung adenocarcinoma, suggesting the role of bioactive components in RevX solution. To further explore whether the bioactive components in RevX solution exhibit other biological activities, such as antiviral effects, we investigated its inhibitory effect on the Mpro of SARS-CoV-2 virus. We report herein that the solid extract of the RevX solution exhibits an efficacious Mpro inhibitory activity, with IC50 of 2.07 ± 0.38 μg/mL. Molecular docking of sterol-like components in the RevX extracts identified by MS shows that the three sterol-like molecules can bind to the active region of the GC376-Mpro complex, supporting the structure-function relationship. Combined with its ability to significantly alleviate the body's immunity decline and to inhibit the activity of SARS-CoV-2 Mpro, RevX solution may provide a possible alternative supportive treatment for patients with COVID-19.

The soluble N-terminal autoinhibitory module of the A1 domain in von Willebrand factor partially suppresses its catch bond with glycoprotein Ibα in a sandwich complex.

von Willebrand factor (VWF) senses and responds to the hemodynamic forces to interact with the circulatory system and platelets in hemostasis and thrombosis. The dark side of this mechanobiology is implicated in atherothrombosis, stroke, and, more recently, the COVID-19 thrombotic symptoms. The force-responsive element controlling VWF activation predominantly resides in the N terminal auto-inhibitory module (N-AIM) flanking its A1 domain. Nevertheless, the detailed mechano-chemistry of soluble VWF N-AIM is poorly understood at the sub-molecular level as it is assumed to be unstructured loops. Using the free molecular dynamics (MD) simulations, we first predicted a hairpin-like structure of the soluble A1 N-AIM derived polypeptide (Lp; sequences Q1238-E1260). Then we combined molecular docking and steered molecular dynamics (SMD) simulations to examine how Lp regulates the A1-GPIbα interaction under tensile forces. Our simulation results indicate that Lp suppresses the catch bond in a sandwich complex of A1-Lp-GPIbα yet contributes an additional catch-bond residue D1249. To experimentally benchmark the binding kinetics for A1-GPIbα in the absence or presence of Lp, we conducted the force spectroscopy-biomembrane force probe (BFP) assays. We found similar suppression on the A1-GPIbα catch bond with soluble Lp in presence. Clinically, as more and more therapeutic candidates targeting the A1-GPIbα axis have entered clinical trials to treat patients with TTP and acute coronary syndrome, our work represents an endeavor further towards an effective anti-thrombotic approach without severe bleeding side effects as most existing drugs suffer.

Peculiar evolution of the Monkeypox virus genomes

We compare the evolution of 14 genomes of monkeypox viruses including that of May 2022 that is currently spreading among humans in numerous countries outside Africa. Our aim was to discover mutations and other viral evolutions (recombination) of the virus genome that may explain the sudden impact of this epidemic circulating at very low-level and alert on its potential pathogenic character. We have evidenced the presence of a succession of a large number of T bases between the DNA-dependent RNA polymerase subunit rpo132 and the cowpox A-type inclusion protein, progressively rising from the absence of a characteristically long pattern of T-bases found in succession (≤ 10) in the early genomes of 1971, up to the 19 T-base sequence in the Israel 2018 reference strain and the 30 T bases thereafter in the 2022 strains. We find a complementary match for this long sequence of T bases only in the simian hemorrhagic encephalitis virus, at the 3’ end of the genome with a long succession of 28 A-bases after the stop codon. More strikingly, we find that the corresponding 10 phenyl-alanine aa chain is reported as matching uniquely (E≤0.001) a hypothetical protein element in Plasmodium falciparum, Yersinia pestis, Escherichia coli and Penicillium nordicum. We wonder whether this region of the monkeypox genome situated right upstream this long T-repeat may potentially code for a not yet identified polypeptide sequences with a functional role.

Coordination of -1 programmed ribosomal frameshifting by transcript and nascent chain features revealed by deep mutational scanning.

Programmed ribosomal frameshifting (PRF) is a translational recoding mechanism that enables the synthesis of multiple polypeptides from a single transcript. During translation of the alphavirus structural polyprotein, the efficiency of −1PRF is coordinated by a ‘slippery’ sequence in the transcript, an adjacent RNA stem–loop, and a conformational transition in the nascent polypeptide chain. To characterize each of these effectors, we measured the effects of 4530 mutations on −1PRF by deep mutational scanning. While most mutations within the slip-site and stem–loop reduce the efficiency of −1PRF, the effects of mutations upstream of the slip-site are far more variable. We identify several regions where modifications of the amino acid sequence of the nascent polypeptide impact the efficiency of −1PRF. Molecular dynamics simulations of polyprotein biogenesis suggest the effects of these mutations primarily arise from their impacts on the mechanical forces that are generated by the translocon-mediated cotranslational folding of the nascent polypeptide chain. Finally, we provide evidence suggesting that the coupling between cotranslational folding and −1PRF depends on the translation kinetics upstream of the slip-site. These findings demonstrate how −1PRF is coordinated by features within both the transcript and nascent chain.

Programmable viscoelasticity in protein-RNA condensates with disordered sticker-spacer polypeptides

Liquid-liquid phase separation of multivalent proteins and RNAs drives the formation of biomolecular condensates that facilitate membrane-free compartmentalization of subcellular processes. With recent advances, it is becoming increasingly clear that biomolecular condensates are network fluids with time-dependent material properties. Here, employing microrheology with optical tweezers, we reveal molecular determinants that govern the viscoelastic behavior of condensates formed by multivalent Arg/Gly-rich sticker-spacer polypeptides and RNA. These condensates behave as Maxwell fluids with an elastically-dominant rheological response at shorter timescales and a liquid-like behavior at longer timescales. The viscous and elastic regimes of these condensates can be tuned by the polypeptide and RNA sequences as well as their mixture compositions. Our results establish a quantitative link between the sequence- and structure-encoded biomolecular interactions at the microscopic scale and the rheological properties of the resulting condensates at the mesoscale, enabling a route to systematically probe and rationally engineer biomolecular condensates with programmable mechanics.

MRNA codon optimization with quantum computers.

Reverse translation of polypeptide sequences to expressible mRNA constructs is a NP-hard combinatorial optimization problem. Each amino acid in the protein sequence can be represented by as many as six codons, and the process of selecting the combination that maximizes probability of expression is termed codon optimization. This work investigates the potential impact of leveraging quantum computing technology for codon optimization. A Quantum Annealer (QA) is compared to a standard genetic algorithm (GA) programmed with the same objective function. The QA is found to be competitive in identifying optimal solutions. The utility of gate-based systems is also evaluated using a simulator resulting in the finding that while current generations of devices lack the hardware requirements, in terms of both qubit count and connectivity, to solve realistic problems, future generation devices may be highly efficient.

Cytotopic (Cyto-) IL-15 as a New Immunotherapy for Prostate Cancer: Recombinant Production in Escherichia coli and Purification.

Interleukin-15 (IL-15) is a cytokine previously suggested as a potential immunotherapy for cancer treatment. IL-15 can effectively reduce tumor growth in many preclinical tumor models including prostate cancer. This is due to its ability to expand and activate immune cells, such as CD8+ T cells and natural killer cells. To increase the potency of IL-15, we have engineered a protein variant that can be modified to localize and be retained in tissues where it is administered. However, the production of recombinant IL-15, the purity, and correct refolding of the final protein is not always ideal. In the current study, we aimed to optimize the methodology for production and purification of a modified recombinant human IL-15 and investigate the efficacy of the produced protein in the treatment of prostate tumors. Human IL-15 with its polypeptide sequence modified at the C-terminus to enable thiol conjugation with membrane localizing peptides, was produced in E. coli and purified using mild denaturing conditions (2M urea) from a washing step or from solubilization of inclusion bodies. The purified protein from the wash fraction was conjugated to a myristoylated peptide to form a membrane-localizing IL-15 (cyto-IL-15). The efficacy of cyto-IL-15 was investigated in subcutaneous TRAMP-C2 prostate tumors in mice and compared with cyto-IL-15 derived from protein purified from inclusion bodies (cyto-IL-15 Gen). When mild denaturing conditions were used for purification, the largest amount of IL-15 was collected from the wash fraction and a smaller amount from inclusion bodies. The protein from the wash fraction was mainly present as a monomer, whereas the one from inclusion bodies formed homodimers and higher complexes. After cytotopic modification, the purified IL-showed great efficacy in delaying prostate tumor growth (∼50%) and increased mice survival by ∼1.8-fold compared with vehicle. This study demonstrates an alternative, inexpensive and efficient method to produce and purify a modified version of IL-15 using mild denaturing conditions. This IL-15, when cytotopically modified, showed great efficacy as a monotherapy in prostate tumors in mice further highlighting the potential of IL-15 as a cancer immunotherapy.

Selective destabilization of polypeptides synthesized from NMD-targeted transcripts.

The translation of mRNAs that contain a premature termination codon (PTC) generates truncated proteins that may have toxic dominant negative effects. Nonsense-mediated decay (NMD) is an mRNA surveillance pathway that degrades PTC-containing mRNAs to limit the production of truncated proteins. NMD activation requires a ribosome terminating translation at a PTC, but what happens to the polypeptides synthesized during the translation cycle needed to activate NMD is incompletely understood. Here, by establishing reporter systems that encode the same polypeptide sequence before a normal termination codon or PTC, we show that termination of protein synthesis at a PTC is sufficient to selectively destabilize polypeptides in mammalian cells. Proteasome inhibition specifically rescues the levels of nascent polypeptides produced from PTC-containing mRNAs within an hour, but also disrupts mRNA homeostasis within a few hours. PTC-terminated polypeptide destabilization is also alleviated by depleting the central NMD factor UPF1 or SMG1, the kinase that phosphorylates UPF1 to activate NMD, but not by inhibiting SMG1 kinase activity. Our results suggest that polypeptide degradation is linked to PTC recognition in mammalian cells and clarify a framework to investigate these mechanisms.

A nascent polypeptide sequence modulates DnaA translation elongation in response to nutrient availability.

The ability to regulate DNA replication initiation in response to changing nutrient conditions is an important feature of most cell types. In bacteria, DNA replication is triggered by the initiator protein DnaA, which has long been suggested to respond to nutritional changes; nevertheless, the underlying mechanisms remain poorly understood. Here, we report a novel mechanism that adjusts DnaA synthesis in response to nutrient availability in Caulobacter crescentus. By performing a detailed biochemical and genetic analysis of the dnaA mRNA, we identified a sequence downstream of the dnaA start codon that inhibits DnaA translation elongation upon carbon exhaustion. Our data show that the corresponding peptide sequence, but not the mRNA secondary structure or the codon choice, is critical for this response, suggesting that specific amino acids in the growing DnaA nascent chain tune translational efficiency. Our study provides new insights into DnaA regulation and highlights the importance of translation elongation as a regulatory target. We propose that translation regulation by nascent chain sequences, like the one described, might constitute a general strategy for modulating the synthesis rate of specific proteins under changing conditions.

Single nucleotide translation without ribosomes.

The translation of messenger RNA sequences into polypeptide sequences according to the genetic code is central to life. How this process, which relies on the ribosomal machinery, arose from much simpler precursors is unclear. Here, we demonstrate that single nucleotides charged with an amino acid couple with amino acids linked to the 5'-terminus of an RNA primer in reactions directed by the nucleotides of an RNA template in dilute aqueous solution at 0 °C. When a mixture of U-Val, A-Gly and G-Leu competed for coupling to Gly-RNA, base pairing dictated which dipeptide sequence formed preferentially. The resulting doubly anchored dipeptides can retain their link to the primer for further extension or can be fully released under mild acidic conditions. These results show that a single-nucleotide-based form of translation exists that requires no more than oligoribonucleotides and anchored amino acids.

Constructing Brain Aβ-Targeting Nanoparticles Loaded with EGCG for Treating Alzheimer's Disease in Mice

To construct a nanodelivery system surface-modified with RD2 peptide (polypeptide sequence PTLHTHNRRRRR) for brain tissue penetration and β-amyloid (Aβ) binding. Epigallocatechin-3-gallate (EGCG) was selected for encapsulation in the targeted delivery system and its therapeutic potential for Alzheimer's disease (AD) was investigated. EGCG-load nanoparticles (NP/EGCG), NP/EGCG with RD2 peptide surface modification (RD2-NP/EGCG), as well as RD2 peptide-modified blank nanoparticles (RD2-NP) were prepared and characterized. Thioflavin T assay was done to assess the ability of RD2-NP to bind with Aβ and ex vivo imaging was conducted to evaluate the distribution of RD2-NP in brain lesion sites. The AD mice model was established by injecting oligomeric Aβ 42 in the bilateral hippocampi of ICR mice. Then AD mice were administered intravenously through the tail vein with normal saline, EGCG solution, NP/EGCG or RD2-NP/EGCG for 28 d, respectively, and the Morris water maze tests were performed to assess the spatial memory of mice. Subsequently, RT-PCR method was used to determine the mRNA levels of tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) in the hippocampus of the mice, and the morphological changes of hippocampal neurons were observed with Nissl staining. Additionally, the pathological changes of heart, liver, spleen, lung, and kidney were characterized by hematoxylin-eosin (HE) staining. The particle diameter of the prepared RD2-NP/EGCG was (204.83±2.80) nm and the zeta potential was -23.88 mV. The encapsulation efficiency and drug loading capacity were 94.39% and 5.90%, respectively. The RD2 peptide modification has no significant effect on the physiochemical properties of the nanoparticles. RD2-NP had good Aβ binding ability, and it could be concentrated in hippocampus and cerebral cortex, the most common Aβ deposition sites. The four-week RD2-NP/EGCG treatment significantly decreased the expression of the pro-inflammatory cytokine TNF-α and IL-1β, restored neuronal losses and hippocampal damage, and ameliorated spatial memory impairment in AD model mice. Moreover, treatment with the RD2-NP/EGCG did not present organ toxicity. Surface modified RD2 peptide nanodelivery system can efficiently deliver drugs to AD lesions and improve the therapeutic effect of EGCG on AD.