Nanomaterials-mediated lysosomal regulation: a robust protein-clearance approach for the treatment of Alzheimer's disease.

Alzheimer's disease is a debilitating, progressive neurodegenerative disorder characterized by the progressive accumulation of abnormal proteins, including amyloid plaques and intracellular tau tangles, primarily within the brain. Lysosomes, crucial intracellular organelles responsible for protein degradation, play a key role in maintaining cellular homeostasis. Some studies have suggested a link between the dysregulation of the lysosomal system and pathogenesis of neurodegenerative diseases, including Alzheimer's disease. Restoring the normal physiological function of lysosomes hold the potential to reduce the pathological burden and improve the symptoms of Alzheimer's disease. Currently, the efficacy of drugs in treating Alzheimer's disease is limited, with major challenges in drug delivery efficiency and targeting. Recently, nanomaterials have gained widespread use in Alzheimer's disease drug research owing to their favorable physical and chemical properties. This review aims to provide a comprehensive overview of recent advances in using nanomaterials (polymeric nanomaterials, nanoemulsions, and carbon-based nanomaterials) to enhance lysosomal function in treating Alzheimer's disease. This review also explores new concepts and potential therapeutic strategies for Alzheimer's disease through the integration of nanomaterials and modulation of lysosomal function. In conclusion, this review emphasizes the potential of nanomaterials in modulating lysosomal function to improve the pathological features of Alzheimer's disease. The application of nanotechnology to the development of Alzheimer's disease drugs brings new ideas and approaches for future treatment of this disease.

Engineering psychrophilic polymerase for nanopore long-read sequencing.

Unveiling the potential application of psychrophilic polymerases as candidates for polymerase-nanopore long-read sequencing presents a departure from conventional choices such as thermophilic Bacillus stearothermophilus (Bst) renowned for its limitation in temperature and mesophilic Bacillus subtilis phage (phi29) polymerases for limitations in strong exonuclease activity and weak salt tolerance. Exploiting the PB-Bst fusion DNA polymerases from Psychrobacillus (PB) and Bacillus stearothermophilus (Bst), our structural and biochemical analysis reveal a remarkable enhancement in salt tolerance and a concurrent reduction in exonuclease activity, achieved through targeted substitution of a pivotal functional domain. The sulfolobus 7-kDa protein (Sso7d) emerges as a standout fusion domain, imparting significant improvements in PB-Bst processivity. Notably, this study elucidates additional functional sites regulating exonuclease activity (Asp43 and Glu45) and processivity using artificial nucleotides (Glu266, Gln283, Leu334, Glu335, Ser426, and Asp430). By disclosing the intricate dynamics in exonuclease activity, strand displacement, and artificial nucleotide-based processivity at specific functional sites, our findings not only advance the fundamental understanding of psychrophilic polymerases but also provide novel insights into polymerase engineering.

Development of a marker recyclable CRISPR/Cas9 system for scarless and multigene editing in Fusarium fujikuroi.

Iterative metabolic engineering of Fusarium fujikuroi has traditionally been hampered by its low homologous recombination efficiency and scarcity of genetic markers. Thus, the clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated proteins (Cas9) system has emerged as a promising tool for precise genome editing in this organism. Some integrated CRISPR/Cas9 strategies have been used to engineer F. fujikuroi to improve GA3 production capabilities, but low editing efficiency and possible genomic instability became the major obstacle. Herein, we developed a marker recyclable CRISPR/Cas9 system for scarless and multigene editing in F. fujikuroi. This system, based on an autonomously replicating sequence, demonstrated the capability of a single plasmid harboring all editing components to achieve 100%, 75%, and 37.5% editing efficiency for single, double, and triple gene targets, respectively. Remarkably, even with a reduction in homologous arms to 50 bp, we achieved a 12.5% gene editing efficiency. By employing this system, we successfully achieved multicopy integration of the truncated 3-hydroxy-3-methyl glutaryl coenzyme A reductase gene (tHMGR), leading to enhanced GA3 production. A key advantage of our plasmid-based gene editing approach was the ability to recycle selective markers through a simplified protoplast preparation and recovery process, which eliminated the need for additional genetic markers. These findings demonstrated that the single-plasmid CRISPR/Cas9 system enables rapid and precise multiple gene deletions/integrations, laying a solid foundation for future metabolic engineering efforts aimed at industrial GA3 production.

Lattice-based mesoscale simulations and mean-field theory of cell membrane adhesion.

Adhesion of cell membranes involves multi-scale phenomena, ranging from specific molecular binding at Angstrom scale all the way up to membrane deformations and phase separation at micrometer scale. Consequently, theory and simulations of cell membrane adhesion require multi-scale modeling and suitable approximations that capture the essential physics of these phenomena. Here, we present a mesoscale model for membrane adhesion which we have employed in a series of our recent studies. This model quantifies, in particular, how nanoscale lipid clusters physically affect and respond to the intercellular receptor-ligand binding that mediates membrane adhesion. The goal of this Chapter is to present all details and subtleties of the mean-field theory and Monte Carlo simulations of this mesoscale model, which can be used to further explore physical phenomena related to cell membrane adhesion.

Identification of two novel HIV-1 unique recombinant forms (CRF01_AE/CRF07_BC) and genomic characterization in Tongzhou district of Beijing, China.

Continuous recombination and variation during replication could lead to rapid evolution and genetic diversity of HIV-1. Some studies had identified that it was easy to develop new recombinant strains of HIV-1 among the populations of men who have sex with men (MSM). Surveillance of genetic variants of HIV-1 in key populations was crucial for comprehending the development of regional HIV-1 epidemics. The finding was reported the identification of two new unique recombinant forms (URF 20110561 and 21110743) from individuals infected with HIV-1 in Tongzhou, Beijing in 2020-2022. Sequences of near full-length genome (NFLG) were amplified, then identification of amplification products used phylogenetic analyses. The result showed that CRF01_AE was the main backbone of 20110561 and 21110743. In the gag region of the virus, 20110561 was inserted two fragments from CRF07_BC, while in the pol and tat regions of the virus, 21110743 was inserted four fragments from CRF07_BC. The CRF01_AE parental origin in the genomes of the two URFs was derived from the CRF01_AE Cluster 4. In the phylogenetic tree, the CRF07_BC parental origin of 20110561 clustered with 07BC_N and the CRF07_BC parental origin of 21110743 clustered with 07BC_O. In summary, the prevalence of novel second-generation URFs of HIV-1 was monitored in Tongzhou, Beijing. The emergence of the novel CRF01_AE/CRF07_BC recombination demonstrated that there was a great significance of continuous monitoring of new URFs in MSM populations to prevent and control the spreading of new HIV-1 URFs.

In Situ Preparation of Metallic Copper Nanosheets/Carbon Paper Sensitive Electrodes for Low-Potential Electrochemical Detection of Nitrite.

In the realm of electrochemical nitrite detection, the potent oxidizing nature of nitrite typically necessitates operation at high detection potentials. However, this study introduces a novel approach to address this challenge by developing a highly sensitive electrochemical sensor with a low reduction detection potential. Specifically, a copper metal nanosheet/carbon paper sensitive electrode (Cu/CP) was fabricated using a one-step electrodeposition method, leveraging the catalytic reduction properties of copper's high occupancy d-orbital. The Cu/CP sensor exhibited remarkable performance in nitrite detection, featuring a low detection potential of -0.05 V vs. Hg/HgO, a wide linear range of 10~1000 µM, an impressive detection limit of 0.079 µM (S/N = 3), and a high sensitivity of 2140 µA mM-1cm-2. These findings underscore the efficacy of electrochemical nitrite detection through catalytic reduction as a means to reduce the operational voltage of the sensor. By showcasing the successful implementation of this strategy, this work sets a valuable precedent for the advancement of electrochemical low-potential nitrite detection methodologies.

Effects of ginseng berry saponins from panax ginseng on glucose metabolism of patients with prediabetes: A randomized, double-blinded, placebo-controlled, crossover trial.

BACKGROUND: Prediabetes strongly increases the risk of type 2 diabetes and cardiovascular events. However, lifestyle intervention, the first-line treatment for prediabetes currently, was inconsistently beneficial for glucose metabolism, and the conventional medicines, such as metformin, is controversial for prediabetes due to the possible side effects. PURPOSE: This study was designed to evaluate the effects of Zhenyuan Capsule, a Chinese patented medicine consisting of ginseng berry saponins extracted from the mature berry of Panax Ginseng, on the glucose metabolism of prediabetic patients as a complementary therapy. STUDY DESIGN AND METHODS: In this randomized, double-Blinded, placebo-controlled, crossover trial, 195 participants with prediabetes were randomized 1:1 to receive either placebo followed by Zhenyuan Capsule, or vice versa, alongside lifestyle interventions. Each treatment period lasted 4 weeks with a 4-week washout period in between. The primary outcomes were the changes in fasting plasma glucose (FPG) and 2-h postprandial plasma glucose (2-h PG) from baseline. Secondary outcomes includes the changes in fasting and 2-h postprandial insulin and C-peptide, the homeostatic model assessment-insulin resistance (HOMA-IR) index and quantitative insulin sensitivity check index (QUICKI) from baseline. Blood lipids and adverse events were also assessed. RESULTS: Compared with placebo, Zhenyuan Capsule caused remarkable reduction in 2-h PG (-0.98 mmol/l) after adjusting treatment order. Zhenyuan Capsule also reduced the fasting and 2-h postprandial levels of insulin and C-peptide, lowered HOMA-IR index (-1.26), and raised QUICKI index (+0.012) when compared to placebo. Additionally, a significant increase in high density lipoprotein cholesterol (HDL-C; +0.25 mmol/l) was found in patients with Zhenyuan Capsule. No serious adverse event occurred during the study. CONCLUSIONS: Among prediabetic patients, Zhenyuan Capsule further reduced 2-h PG level, alleviated insulin resistance and raised HDL-C level on the background of lifestyle interventions. The study protocol is registered with the Chinese Clinical Trial Registry (ChiCTR2000034000).

Auricular point acupressure for managing postoperative pain and reducing anxiety in patients with perianal abscesses.

OBJECTIVE: The objective of this study is to assess the efficacy of auricular point acupressure in relieving postoperative pain and reducing anxiety among patients with perianal abscesses. METHODS: We included 61 patients with perianal abscesses who were admitted to the Nantong First People's Hospital between July 2019 and June 2020 and were scheduled to undergo one-stage radical surgery. We divided them into the treatment group (n = 31), where patients were administered preoperative auricular acupressure targeting the bilateral Shenmen, subcortical, and other points. They were instructed to apply pressure five to six times per day, each time for about 3-5 min. Patients in the control group (n = 30) received routine preoperative preparation. The treatment duration for both groups was one week. We compared the two groups using the pain visual analog scale (VAS) scores, the use of additional postoperative analgesics, and scores on the Hamilton anxiety and depression scales pre- and post-surgery at 6 h, 24 h, 48 h, 72 h, and 1 week after surgery, as well as at the time of the first bowel movement. RESULTS: Patients in the treatment group reported lower VAS scores than those of the control group at 48 h, 72 h, 1 week, and at the first defecation post-surgery, and the differences were statistically significant (all P < 0.05). Additional postoperative analgesics were used in seven patients in the treatment group (22.58 %) and in 10 patients in the control group (33.33 %). The difference between the two groups was not statistically significant (χ2 = 0.88, P = 0.35). Postoperative scores for the Hamilton Anxiety Rating Scale (HAM-A) and the Hamilton Depression Rating Scale (HAM-D) in the treatment group were significantly lower than those in the control group (P < 0.05). CONCLUSION: The results of this study demonstrated that auricular point acupressure was effective in alleviating postoperative pain in patients with perianal abscesses and simultaneously reduced their postoperative psychological stress reactions. This dual effect provided both pain relief and a reduction of anxiety with fewer adverse reactions, making it a safe and effective treatment option.

Body part categorical matching in chimpanzees (Pan troglodytes).

Humans categorize body parts, reflecting our knowledge about bodies, and this could be useful in higher-level activities involving bodies. We tested whether humans' closest living relatives-chimpanzees-have the same ability using touchscreen tasks, focusing on the major parts: heads, torsos, arms, and legs. Six chimpanzees were trained to perform a body part matching-to-sample task using sets of pictures of chimpanzee bodies, where in each trial, the sample and choice pictures were the same. Five passed the training and received the test sessions, where three trial types were mixed: trained same-individual picture pairs; novel same-individual picture pairs; and novel different-individual picture pairs. All participants performed better than the chance level in all conditions and for all body parts. Further analyses showed differences in performance when the samples were different body parts. For example, the results revealed better performances for heads and torsos than arms and legs in "novel different-individual pairs". The study showed that chimpanzees can visually match and categorize body parts in this experiment setting, even across different chimpanzees' bodies, suggesting potential biological understanding. Different performances for body parts suggested a deviated categorization from humans. We hope this study will inspire future research on the evolution of body perception.

Surface Coating of NCM523 Cathode Electrodes by the Difunctional Block Copolymer/Lithium Salt Composites.

Nickel-rich layered oxide cathodes, such as LiNi0.5Co0.2Mn0.3O2 (NCM523), are prevalent in high-power batteries owing to their high energy density. However, these cathodes suffer from undesirable side reactions occurring at the cathode/liquid electrolyte interface, leading to inferior interface stability and poor cycle life. To address these issues, herein, an amphiphilic diblock copolymer poly(dimethylsiloxane)-block-poly(acrylic acid) (PDMS-b-PAA) along with lithium bis(trifluoromethanesulfonyl)imide (LiTFSI) is utilized for modifying the electrode surface. This modification causes a thin and stable cathode-electrolyte interface (CEI) on the surface of NCM523 particles, as evidenced by XPS, TEM, and EIS analysis. The introduction of this modified interface successfully suppresses the capacity fading of NCM523. After 200 cycles at a rate of 1.0 C, the capacity of the modified NCM523 cathode is 108.7 mAh g-1, with a capacity retention of 82.8%, while the control samples without the polymer modification display a capacity retention of 72.7%. These results outline the distinct advantage of electrode surface modification with diblock copolymers/LiTFSI for the stabilization of Ni-rich layered oxide cathodes.

Development of an accurate hand-held sensing platform for nitrite detection based on nitrogen-doped carbon dots.

As is well known, excessive nitrite can seriously pollute the environment and can harm human health. Although existing methods can be used to determine nitrite content, they still have some drawbacks, such as relatively complicated operation and expensive equipment. Herein, a hand-held sensing platform (HSP) for NO2- determination was developed. First, ammonia-rich nitrogen-doped carbon dots with orange-yellow emission were designed and synthesised, which were suitable as fluorescent probes because of their good optical properties and stability. Then, the HSP based on fluorescence using photoelectric conversion technology was designed and manufactured using three-dimensional printing technology. Under optimum conditions, the voltage (V/V0) of the proposed HSP showed good linearity for NO2- detection in the range of 10-500 µM, with a detection limit of 1.95 µM. This portable sensor showed good stability, accuracy and reliability in detecting actual water and meat samples, which may ensure food safety in practical applications. Moreover, the HSP is compact, portable and easily assembled and is suitable for on-site real-time detection, which shows great application potential and prospects.

Collaborative Fabrication of High-Quality Perovskite Films for Efficient Solar Modules through Solvent Engineering and Vacuum Flash System.

The vacuum flash solution method has gained widespread recognition in the preparation of perovskite thin films, laying the foundation for the industrialization of perovskite solar cells. However, the low volatility of dimethyl sulfoxide and its weak interaction with formamidine-based perovskites significantly hinder the preparation of cell modules and the further improvement of photovoltaic performance. In this study, we describe an efficient and reproducible method for preparing large-scale, highly uniform formamidinium lead triiodide (FAPbI3) perovskite films. This is achieved by accelerating the vacuum flash rate and leveraging the complex synergism. Specifically, we designed a dual pump system to accelerate the depressurization rate of the vacuum system and compared the quality of perovskite film formed at different depressurization rates. Further, to overcome the limitations posed by DMSO, we substituted N-methylpyrrolidone as the ligand solvent, creating a stable intermediate complex phase. After annealing, it can be transformed into a uniform and pinhole-free FAPbI3 film. Due to the superior quality of these films, the large area perovskite solar module achieved a power conversion efficiency of 22.7% with an active area of 21.4 cm2. Additionally, it obtained an official certified efficiency of 22.1% with an aperture area of 22 cm2, and it demonstrated long-term stability.

Acquired reactive perforating collagenosis triggered by trauma with eosinophilia: a case report and literature review.

Acquired reactive perforating collagenosis (ARPC) is a rare dermatological disorder condition defined by the perforation of altered collagen fibers through the epidermis. The presence of underlying conditions such as diabetes or renal disease is helpful in the ARPC diagnosis. Although skin rashes related to ARPC have been reported, the exact causative factors and mechanisms remain unclear. Here, we present a unique case of ARPC triggered by trauma in a 67-year-old male without concurrent systemic alterations. The diagnosis of ARPC with eosinophilia was made following comprehensive diagnostic testing, including clinical presentation, histological results, and blood tests, ruling out other possible diseases. Intriguingly, the histopathological examination revealed collagen penetration into the epidermis at different tissue sections. In addition, we reviewed existing literature on ARPC, which documented the causation. To help confirm the diagnosis, clinicians have to pay attention to traumatic triggers for ARPC and its rare manifestation with eosinophilia.

Establishment of a promising vitiligo mouse model for pathogenesis and treatment studies.

AIMS: Vitiligo is a chronic dermatological condition characterized by the progressive loss of melanocytes, for which traditional therapy has shown limited efficacy. This study aimed to establish a vitiligo model with easy operability, high repeatability, and stable depigmentation to provide a foundation for studying the pathogenesis and developing novel therapies for vitiligo. METHODS: (1) Establishing vitiligo model: Firstly, deliver B16F10 cells to the back skin of C57BL/6 J via intradermal injection (day 0), and the CD4 depletion antibody was injected intraperitoneally on day 4 and 10. Secondly, the melanoma was surgically removed on day 12. Thirdly, CD8 antibody was administered intraperitoneally every fourth day till day 30. (2) Identification of vitiligo model: H&E staining, immunohistochemistry, and immunofluorescence were used to detect the melanocytes. The melanin was detected by transmission electron microscopy (TEM), Lillie ferrous sulfate staining and L-DOPA staining. RESULTS: (1) The back skin and hair began to appear white on day 30. Melanin loss reached peak on day 60; (2) Hematoxylin and eosin (H&E) staining, immunohistochemistry and immunofluorescence results showed melanocytes were reduced. L-DOPA staining, Lillie ferrous sulfate staining and TEM results showed that melanin decreased in the epidermis. CONCLUSION: We successfully establishment a vitiligo mouse model which can be more capable to simulate the pathogenesis of human vitiligo and provide an important basis for the study of pathogenesis and therapy of vitiligo.

Inhibitor of cardiolipin biosynthesis-related enzyme MoGep4 confers broad-spectrum anti-fungal activity.

Plant pathogens cause devastating diseases, leading to serious losses to agriculture. Mechanistic understanding of pathogenesis of plant pathogens lays the foundation for the development of fungicides for disease control. Mitophagy, a specific form of autophagy, is important for fungal virulence. The role of cardiolipin, mitochondrial signature phospholipid, in mitophagy and pathogenesis is largely unknown in plant pathogenic fungi. The functions of enzymes involved in cardiolipin biosynthesis and relevant inhibitors were assessed using a set of assays, including genetic deletion, plant infection, lipidomics, chemical-protein interaction, chemical inhibition, and field trials. Our results showed that the cardiolipin biosynthesis-related gene MoGEP4 of the rice blast fungus Magnaporthe oryzae regulates growth, conidiation, cardiolipin biosynthesis, and virulence. Mechanistically, MoGep4 regulated mitophagy and Mps1-MAPK phosphorylation, which are required for virulence. Chemical alexidine dihydrochloride (AXD) inhibited the enzyme activity of MoGep4, cardiolipin biosynthesis and mitophagy. Importantly, AXD efficiently inhibited the growth of 10 plant pathogens and controlled rice blast and Fusarium head blight in the field. Our study demonstrated that MoGep4 regulates mitophagy, Mps1 phosphorylation and pathogenesis in M. oryzae. In addition, we found that the MoGep4 inhibitor, AXD, displays broad-spectrum antifungal activity and is a promising candidate for fungicide development.

Detection of GSH with a dual-mode biosensor based on carbon quantum dots prepared from dragon fruit peel and the T-Hg(II)-T mismatch.

Glutathione (GSH) is commonly used as a diagnostic biomarker for many diseases. In this study, based on carbon quantum dots prepared from dragon fruit peel (D-CQDs) and the T-Hg(II)-T mismatch, a dual-mode biosensor was developed for the detection of GSH. This system consists of two single-stranded DNA (ssDNA). DNA1 was the T-rich sequence; DNA2 was attached to streptavidin-coated magnetic beads and consisted of T-rich and G-rich fragments. Due to the presence of Hg(II), the T-Hg(II)-T mismatch was formed between T-rich fragments of two ssDNA. In the presence of GSH, Hg(II) detached from dsDNA and bound with GSH to form a new complex. The G-rich fragment assembled with the hemin shed from D-CQDs to form the G-quadruplex/hemin complex. At this time, in fluorescence mode, the fluorescence of D-CQDs quenched by hemin could be restored. In colorimetric mode, after the magnetic beads separate, a visual signal could be produced by catalyzing the oxidation of ABTS using the peroxide-like activity of the G-quadruplex/hemin complex. This biosensor in both fluorescence mode and colorimetric mode had excellent selectivity and sensitivity, and the limit of detection was 0.089 µM and 0.26 µM for GSH, respectively. Moreover, the proposed dual-mode biosensor had good application prospects for detection of GSH.

Chromomycins from soil-derived Streptomyces sp. inhibit the growth of human non-small cell lung cancer cells by targeting c-FLIP.

Three chromomycin derivatives, chromomycins A3 (1, CA3), A5 (2, CA5), and monodeacetylchromomycin A3 (3, MDA-CA3), were identified from the soil-derived Streptomyces sp. CGMCC 26516. A reinvestigation of the structure of CA5 is reported, of which the absolute configuration was unambiguously determined for the first time to be identical with that of CA3 based on nuclear magnetic resonance (NMR) data analysis as well as NMR and electronic circular dichroism calculations. Compounds 1-3 showed potent cytotoxicity against the non-small-cell lung cancer (NSCLC) cells (A549, H460, H157-c-FLIP, and H157-LacZ) and down-regulated the protein expression of c-FLIP in A549 cells. The IC50 values of chromomycins in H157-c-FLIP were higher than that in H157-LacZ. Furthermore, si-c-FLIP promoted anti-proliferation effect of chromomycins in NSCLC cells. In nude mice xenograft model, 1 and 2 both showed more potent inhibition on the growth of H157-lacZ xenografts than that of H157-c-FLIP xenografts. These results verify that c-FLIP mediates the anticancer effects of chromomycins in NSCLC.

Ubiquitin-specific protease 1 facilitates hepatocellular carcinoma progression by modulating mitochondrial fission and metabolic reprogramming via cyclin-dependent kinase 5 stabilization.

Although deubiquitinases (DUBs) have been well described in liver tumorigenesis, their potential roles and mechanisms have not been fully understood. In this study, we identified ubiquitin-specific protease 1 (USP1) as an oncogene with essential roles during hepatocellular carcinoma (HCC) progression. USP1, with elevated expression levels and clinical significance, was identified as a hub DUB for HCC in multiple bioinformatics datasets. Functionally, USP1 overexpression significantly enhanced the malignant behaviors in HCC cell lines and spheroids in vitro, as well as the zebrafish model and the xenograft model in vivo. In contrast, genetic ablation or pharmacological inhibition of USP1 dramatically impaired the phenotypes of HCC cells. Specifically, ectopic USP1 enhanced aggressive properties and metabolic reprogramming of HCC cells by modulating mitochondrial dynamics. Mechanistically, USP1 induced mitochondrial fission by enhancing phosphorylation of Drp1 at Ser616 via deubiquitination and stabilization of cyclin-dependent kinase 5 (CDK5), which could be degraded by the E3 ligase NEDD4L. The USP1/CDK5 modulatory axis was activated in HCC tissues, which was correlated with poor prognosis of HCC patients. Furthermore, Prasugrel was identified as a candidate USP1 inhibitor for targeting the phenotypes of HCC by an extensive computational study combined with experimental validations. Taken together, USP1 induced malignant phenotypes and metabolic reprogramming by modulating mitochondrial dynamics in a CDK5-mediated Drp1 phosphorylation manner, thereby deteriorating HCC progression.

Systemic Administration of Neurotransmitter-Derived Lipidoids-PROTACs-DNA Nanocomplex Promotes Tau Clearance and Cognitive Recovery for Alzheimer's Disease Therapy.

Alzheimer's disease (AD) poses a significant burden on the economy and healthcare systems worldwide. Although the pathophysiology of AD remains debatable, its progression is strongly correlated with the accumulation of tau aggregates. Therefore, tau clearance from brain lesions can be a promising strategy for AD therapy. To achieve this, the present study combined proteolysis-targeting chimera (PROTAC), a novel protein-degradation technique that mediates degradation of target proteins via the ubiquitin-proteasome system, and a neurotransmitter-derived lipidoid (NT-lipidoid) nanoparticle delivery system with high blood-brain barrier-penetration activity, to generate a novel nanomedicine named NPD. Peptide 1, a cationic tau-targeting PROTAC is loaded onto the positively charged nanoparticles using DNA-intercalation technology. The resulting nanomedicine displayed good encapsulation efficiency, serum stability, drug release profile, and blood-brain barrier-penetration capability. Furthermore, NPD potently induced tau clearance in both cultured neuronal cells and the brains of AD mice. Moreover, intravenous injection of NPD led to a significant improvement in the cognitive function of the AD mice, without any remarkable abnormalities, thereby supporting its clinical development. Collectively, the novel nanomedicine developed in this study may serve as an innovative strategy for AD therapy, since it effectively and specifically induces tau protein clearance in brain lesions, which in turn enhances cognition.