Efficient Targeting Research Articles

Rescuing Nucleus Pulposus Cells from ROS Toxic Microenvironment via Mitochondria-Targeted Carbon Dot-Supported Prussian Blue to Alleviate Intervertebral Disc Degeneration.

Intervertebral disc degeneration (IVDD) is invariably accompanied by excessive accumulation of reactive oxygen species (ROS), resulting in progressive deterioration of mitochondrial function and senescence in nucleus pulposus cells (NPCs). Significantly, the main ROS production site in non-immune cells is mitochondria, suggesting mitochondria is a feasible therapeutic target to reverse IVDD. Triphenylphosphine (TPP), which is known as mitochondrial-tropic ligands, is utilized to modify carbon dot-supported Prussian blue (CD-PB) to scavenge superfluous intro-cellular ROS and maintain NPCs at normal redox levels. CD-PB-TPP can effectively escape from lysosomal phagocytosis, permitting efficient mitochondrial targeting. After strikingly lessening the ROS in mitochondria via exerting antioxidant enzyme-like activities, such as superoxide dismutase, and catalase, CD-PB-TPP rescues damaged mitochondrial function and NPCs from senescence, catabolism, and inflammatory reaction in vitro. Imaging evaluation and tissue morphology assessment in vivo suggest that disc height index, mean grey values of nucleus pulposus tissue, and histological morphology are significantly improved in the IVDD model after CD-PB-TPP is locally performed. In conclusion, this study demonstrates that ROS-induced mitochondrial dysfunction and senescence of NPCs leads to IVDD and the CD-PB-TPP possesses enormous potential to rescue this pathological process through efficient removal of ROS via targeting mitochondria, supplying a neoteric strategy for IVDD treatment.

Engineering Self-Assembling Peptide Hydrogel to Enhance the Capacity of Dendritic Cells to Activate In Vivo T-Cell Immunity.

The efficacy of the dendritic cell (DC) has failed to meet expectations thus far, and crucial problems such as the immature state of DCs, low targeting efficiency, insufficient number of dendritic cells, and microenvironment are still the current focus. To address these problems, we developed two self-assembling peptides, RLDI and RQDT, that mimic extracellular matrix (ECM). These peptides can be self-assembled into highly ordered three-dimensional nanofiber scaffold structures, where RLDI can form gelation immediately. In addition, we found that RLDI and RQDT enhance the biological function of DCs, including releasing antigens sustainably, adhering to DCs, promoting the maturation of DCs, and increasing the ability of DC antigen presentation. Moreover, peptide hydrogel-based DC treatment significantly achieved prophylactic and treatment effects on colon cancer. These results have certain implications for the design of new broad-spectrum vaccines in the future.

Biodegradable Covalently Crosslinked Poly[N-(2-Hydroxypropyl) Methacrylamide] Nanogels: Preparation and Physicochemical Properties.

Recently, suitably sized polymer-based nanogels containing functional groups for the binding of biologically active substances and ultimately degradable to products that can be removed by glomerular filtration have become extensively studied systems in the field of drug delivery. Herein, we designed and tailored the synthesis of hydrophilic and biodegradable poly[N-(2-hydroxypropyl) methacrylamide-co-N,N'-bis(acryloyl) cystamine-co-6-methacrylamidohexanoyl hydrazine] (PHPMA-BAC-BMH) nanogels. The facile and versatile dispersion polymerization enabled the preparation of nanogels with a diameter below 50 nm, which is the key parameter for efficient and selective passive tumor targeting. The effects of the N,N'-bis(acryloyl) cystamine crosslinker, polymerization composition, and medium including H2O/MetCel and H2O/EtCel on the particle size, particle size distribution, morphology, and polymerization kinetics and copolymer composition were investigated in detail. We demonstrated the formation of a 38 nm colloidally stable PHPMA-BAC-BMH nanogel with a core-shell structure that can be rapidly degraded in the presence of 10 mM glutathione solution under physiologic conditions. The nanogels were stable in an aqueous solution modeling the bloodstream; thus, these nanogels have the potential to become highly important carriers in the drug delivery of various molecules.

Hepatocyte GPCR signaling regulates IRF3 to control hepatic stellate cell transdifferentiation

BackgroundInterferon Regulatory Factor 3 (IRF3) is a transcription factor that plays a crucial role in the innate immune response by recognizing and responding to foreign antigens. Recently, its roles in sterile conditions are being studied, as in metabolic and fibrotic diseases. However, the search on the upstream regulator for efficient pharmacological targeting is yet to be fully explored. Here, we show that G protein-coupled receptors (GPCRs) can regulate IRF3 phosphorylation through of GPCR-Gα protein interaction.ResultsIRF3 and target genes were strongly associated with fibrosis markers in liver fibrosis patients and models. Conditioned media from MIHA hepatocytes overexpressing IRF3 induced fibrogenic activation of LX-2 hepatic stellate cells (HSCs). In an overexpression library screening using active mutant Gα subunits and Phos-tag immunoblotting, Gαs was found out to strongly phosphorylate IRF3. Stimulation of Gαs by glucagon or epinephrine or by Gαs-specific designed GPCR phosphorylated IRF3. Protein kinase A (PKA) signaling was primarily responsible for IRF3 phosphorylation and Interleukin 33 (IL-33) expression downstream of Gαs. PKA phosphorylated IRF3 on a previously unrecognized residue and did not require reported upstream kinases such as TANK-binding kinase 1 (TBK1). Activation of Gαs signaling by glucagon induced IL-33 production in hepatocytes. Conditioned media from the hepatocytes activated HSCs, as indicated by α-SMA and COL1A1 expression, and this was reversed by pre-treatment of the media with IL-33 neutralizing antibody.ConclusionsGαs-coupled GPCR signaling increases IRF3 phosphorylation through cAMP-mediated activation of PKA. This leads to an increase of IL-33 expression, which further contributes to HSC activation. Our findings that hepatocyte GPCR signaling regulates IRF3 to control hepatic stellate cell transdifferentiation provides an insight for understanding the complex intercellular communication during liver fibrosis progression and suggests therapeutic opportunities for the disease.3Z-4y3zsWdGiZ_62kYezA1Video

A CRISPRi-based genetic resource to study essential Staphylococcus aureus genes.

Staphylococcus aureus is an important clinical pathogen that causes a high number of antibiotic-resistant infections. The study of S. aureus biology, and particularly of the function of essential proteins, is of particular importance to develop new approaches to combat this pathogen. We have optimized a clustered regularly interspaced short palindromic repeat interference (CRISPRi) system that allows efficient targeting of essential S. aureus genes. Furthermore, we have used that system to construct a library comprising 261 strains, which allows the depletion of essential proteins encoded by 200 genes/operons. This library, which we have named Lisbon CRISPRi Mutant Library, should facilitate the study of S. aureus pathogenesis and biology.

The contribution of mRNA targeting to spatial protein localization in bacteria.

About 30% of all bacterial proteins execute their function outside of the cytosol and must be inserted into or translocated across the cytoplasmic membrane. This requires efficient targeting systems that recognize N-terminal signal sequences in client proteins and deliver them to protein transport complexes in the membrane. While the importance of these protein transport machineries for the spatial organization of the bacterial cell is well documented in multiple studies, the contribution of mRNA targeting and localized translation to protein transport is only beginning to emerge. mRNAs can exhibit diverse subcellular localizations in the bacterial cell and can accumulate at sites where new protein is required. This is frequently observed for mRNAs encoding membrane proteins, but the physiological importance of membrane enrichment of mRNAs and the consequences it has for the insertion of the encoded protein have not been explored in detail. Here, we briefly highlight some basic concepts of signal sequence-based protein targeting and describe in more detail strategies that enable the monitoring of mRNA localization in bacterial cells and potential mechanisms that route mRNAs to particular positions within the cell. Finally, we summarize some recent developments that demonstrate that mRNA targeting and localized translation can sustain membrane protein insertion under stress conditions when the protein-targeting machinery is compromised. Thus, mRNA targeting likely acts as a back-up strategy and complements the canonical signal sequence-based protein targeting.

Target setting using an enhanced inverse DEA approach: application to Spanish universities

This paper proposes a non-oriented, non-radial Inverse Data Envelopment Analysis (InvDEA) approach for target setting. The changes of any input and output dimensions may be fixed. In addition to the corresponding multiobjective optimisation model, the approach includes a prior step that checks the feasibility of the input and output changes that are fixed and revises them if necessary. This Pre-InvDEA model uses Goal Programming (GP) and guarantees the feasibility of those changes. The approach also includes a Post-InvDEA multiobjective optimisation model to optimise the input and output changes given in order to guarantee that the computed target is efficient. The overall target-setting approach is conceived as an interactive process so that the three steps (Pre-InvDEA, InvDEA, and Post-InvDEA) may be run more than once until a satisfactory target is determined. The application of the proposed approach to computing efficient targets for Spanish universities is presented.

Facilitated Transport of EGFR Inhibitors Plays an Important Role in Their Cellular Uptake.

Epidermal growth factor receptor (EGFR) is a transmembrane protein commonly targeted by tyrosine kinase inhibitors (TKIs) as a front-line therapy for patients with many cancers including nonsmall cell lung cancer (NSCLC). Effective treatment requires efficient intracellular drug uptake and target binding. However, despite the recent success in the development of new TKI drugs, the mechanisms of uptake for many TKIs are still poorly understood due to the difficulty in imaging and measuring nonfluorescent drug molecules at a subcellular resolution. It has previously been shown that weakly basic TKI drugs are sequestered in lysosomes. Leveraging this property, we apply hyperspectral stimulated Raman scattering imaging to directly visualize and quantify two Food and Drug Administration-approved EGFR inhibitor drugs (lapatinib and afatinib) inside living cells and the changes in their cellular uptake upon the addition of organic cation transporter inhibitors. These single-cell quantitative measurements provide new insight into the role of membrane transporters in the uptake of TKI drugs in living cells.

Self-organized swarm robot for multi-target trapping based on self-regulated density interaction

In swarm robotics, multi-target trapping usually relies on global information or explicit communication, posing a challenge for robots to autonomously self-organize and trap multiple targets with only local perceptual data. We present a self-regulated density-based approach for self-organized multi-target trapping. This method employs density-based negative feedback control and density-distance weighted target selection. Our approach leverages distributed perception, where robots perceive nearby peers within their sensory range, eliminating the need for explicit information exchange and enabling autonomous trapping. During task execution, negative feedback control adjusts swarm density, ensuring it reaches an optimal level. Building on this, individual robots use density fields and relative target positions to select suitable targets, achieving self-regulated dispersed selection and multi-target trapping. We validate our approach through numerical simulations and real-world robot experiments. Results demonstrate stable self-organization, efficient self-regulated dispersed target selection, and successful target trapping, even with a limited number of trapping robots in low-redundancy scenarios.

Wind of change: the impact of REPowerEU policy reforms on gas security

ABSTRACT The Russian invasion of Ukraine was a shock to the EU gas market, as Russian gas supply dwindled and prices spiked. Previous exogenous shocks to the gas market resulted in policy reforms aimed at diversification and reducing dependency on Russian gas. However, their effectiveness was reduced. This study seeks to examine the policy changes under REPowerEU in light of gas security post-invasion. To examine this, three indicators – import dependency, diversification, and gas intensity – are used and examined the REPowerEU policy elements – reduced Russian gas, increased renewables and energy efficiency targets, gas storage requirements, demand reduction and a joint purchasing mechanism. This preliminary analysis highlights similarities in approaches, but also find that the severity of the crisis contributed to more support. The early effectiveness of the policy reforms is questioned, as change appear driven by other factors, such as decisions made by Russia and high gas prices.

Consumer Data Without Compromise: Integrating Differential Privacy and GANs for Privacy-Preserving Digital Marketing

In the rapidly evolving digital marketing landscape, the utilization of consumer data is essential for efficient targeting and personalization of marketing practices. However, the growing concerns regarding user privacy and stringent data protection regulations have created challenges in accessing and using consumer data for marketing purposes. This paper introduces a novel approach that leverages Differential Privacy and Conditional Tabular Generative Adversarial Networks (CTGAN) to address these privacy concerns while maintaining the efficacy of data-driven digital marketing strategies. Our approach amalgamates the strengths of Differential Privacy and CTGAN, applying differential privacy to the original dataset to ensure that extracted data cannot be tied back to individuals. We then train a CTGAN on an open marketing dataset to learn and generate synthetic data of close resemblance. Through extensive empirical analysis, we evaluate the fidelity, utility, and trade-offs of our approach, demonstrating its effectiveness in synthesizing non-Gaussian and multi-modal distributions, and its applicability in real-world classification problems. The research also highlights the complexity of hyperparameter tuning and the importance of a balanced approach in model training. Our findings contribute valuable insights to both the theoretical understanding of generative models and practical guidance for digital marketing practitioners

Ultrasound-activated prodrug-loaded liposome for efficient cancer targeting therapy without chemotherapy-induced side effects.

Off-targeted distribution of chemotherapeutic drugs causes severe side effects, further leading to poor prognosis and patient compliance. Ligand/receptor-mediated targeted drug delivery can improve drug accumulation in the tumor but it always attenuated by protein corona barriers. To address these problems, a radically different strategy is proposed that can leave the off-targeted drugs inactive but activate the tumor-distributed drugs for cancer-targeting therapy in a tumor microenvironment-independent manner. The feasibility and effectiveness of this strategy is demonstrated by developing an ultrasound (US)-activated prodrug-loaded liposome (CPBSN38L) comprising the sonosensitizer chlorin e6 (Ce6)-modified lipids and the prodrug of pinacol boronic ester-conjugated SN38 (PBSN38). Once CPBSN38L is accumulated in the tumor and internalized into the cancer cells, under US irradiation, the sonosensitizer Ce6 rapidly induces extensive production of intracellular reactive oxygen species (ROS), thereby initiating a cascade amplified ROS-responsive activation of PBSN38 to release the active SN38 for inducing cell apoptosis. If some of the injected CPBSN38L is distributed into normal tissues, the inactive PBSN38 exerts no pharmacological activity on normal cells. CPBSN38L exhibited strong anticancer activity in multiple murine tumor models of colon adenocarcinoma and hepatocellular carcinoma with no chemotherapy-induced side effects, compared with the standard first-line anticancer drugs irinotecan and topotecan. This study established a side-effect-evitable, universal, and feasible strategy for cancer-targeting therapy.

Novel ligand conjugated poly(propylene imine) dendrimers for brain targeted delivery of tacrine hydrochloride

Alzheimer's disease (AD) is the most common type of neurodegenerative disorder characterized by extracellular deposition of Amyloid β and intracellular deposition of neurofibrillary tangles. One of the most common etiological factors is rapid and excessive hydrolysis of acetylcholine by acetylcholinesterase (AChE) enzyme. Tacrine is one of the most potent and first USFDA approved centrally acting AChE inhibitor recommended for treatment of AD, but it is no longer in use as it causes severe peripheral side effects, mainly hepatotoxicity. In this research work, novel dendrimeric conjugates were developed with an aim of enhancing the brain targeting efficiency of tacrine and eliminating the peripheral side effects. Poly(propyleneimine) G5.0 dendrimers were conjugated with oleic acid as a brain targeting ligand, and the conjugation was confirmed by Fourier-transform infrared spectroscopy, 1H nuclear magnetic resonance spectroscopy and dynamic light scattering studies. Tacrine hydrochloride was loaded into the plain dendrimer as well as oleic acid conjugated dendrimer by physical encapsulation method. The in vitro AChE inhibitory study showed retention of the AChE inhibition ability of tacrine in dendrimeric conjugates. The safety of the drug loaded conjugates was confirmed by haemolytic, nasal ciliotoxicity and cytotoxicity studies. Further, cellular uptake studies in SH-SY5Y cells showed abundance of green cytoplasmic fluorescence, suggesting enhanced internalization of dendrimeric conjugates. The results of this research work support the further exploration of this novel dendrimers based conjugated delivery system for in vivo studies as a potential alternative to treat AD.

A PEG-assisted membrane coating to prepare biomimetic mesoporous silicon for PET/CT imaging of triple-negative breast cancer

Triple-negative breast cancer (TNBC) diagnosis remains challenging without expressing critical receptors. Cancer cell membrane (CCm) coating has been extensively studied for targeted cancer diagnostics due to attractive features such as good biocompatibility and homotypic tumor-targeting. However, the present study found that widely used CCm coating approaches, such as extrusion, were not applicable for functionalizing irregularly shaped nanoparticles (NPs), such as porous silicon (PSi). To tackle this challenge, we proposed a novel approach that employs polyethylene glycol (PEG)-assisted membrane coating, wherein PEG and CCm are respectively functionalized on PSi NPs through chemical conjugation and physical absorption. Meanwhile, the PSi NPs were grafted with the bisphosphonate (BP) molecules for radiolabeling. Thanks to the good chelating ability of BP and homotypic tumor targeting of cancer CCm coating, a novel PSi-based contrast agent (CCm-PEG-89Zr-BP-PSi) was developed for targeted positron emission tomography (PET)/computed tomography (CT) imaging of TNBC. The novel imaging agent showed good radiochemical purity (∼99 %) and stability (∼95 % in PBS and ∼99 % in cell medium after 48 h). Furthermore, the CCm-PEG-89Zr-BP-PSi NPs had efficient homotypic targeting ability in vitro and in vivo for TNBC. These findings demonstrate a versatile biomimetic coating method to prepare novel NPs for tumor-targeted diagnosis.

An Inducible CRISPR-dCas9-Based Transcriptional Repression System for Cancer Therapy.

Gene therapy has been adapted for improving malignant tumor treatment. However, pharmacotherapies targeting cancer remain limited and are generally inapplicable for rare disease patients. Oleanolic acid (OA) is a plant-derived triterpenoid that is frequently used in Chinese medicine as a safe but slow-acting treatment for many disorders. Here, the congruent pharmacological activities of OA and CRISPR-dCas9 in targeting AURKA or KDM1A and improving disease-specific prognosis and used a synthetic-biology-inspired design principle to engineer a therapeutic gene circuit that enables a concerted action of both drugs are utilized. In particular, the OA-triggered CRISPR-dCas9 transcriptional repression system rapidly and simultaneously attenuated lung and thyroid cancer. Collectively, this work shows that rationally engineered synthetic gene circuits are capable of treating multifactorial diseases in a synergistic manner by multiplexing the targeting efficiencies of single therapeutics.

Effect of ligand and shell densities on the surface structure of core-shell nanoparticles self-assembled from function-spacer-lipid constructs.

Biomolecular corona is the major obstacle to the clinical translation of nanomedicines. Since corona formation is governed by molecular interactions at the nano-bio interface, nanoparticle surface properties such as topography, charge and surface chemistry can be tuned to manipulate biomolecular corona formation. To this end, as the first step towards a deep understanding of the processes of corona formation, it is necessary to develop nanoparticles employing various biocompatible materials and characterize their surface structure and dynamics at the molecular level. In this work, we applied molecular dynamics simulation to study the surface structure of organic core-shell nanoparticles formed by the self-assembly of synthetic molecules composed of a DOPE lipid, a carboxymethylglycine spacer and biotin. Lipid moieties form the hydrophobic core, spacer motifs serve as a hydrophilic shell and biotin residues function as a targeting ligand. By mixing such function-spacer-lipid, spacer-lipid and lipid-only constructs at various molar ratios, densities of the ligand and spacer on the nanoparticle surface were modified. For convenient analysis of the structure and dynamics of all regions of the nanoparticle surface, we compiled topography maps based on atomic coordinates. It was shown that an increase in the density of the shell does not reduce exposure of the core, but increases shell average thickness. Biotin, due to its alkyl valeric acid chain and spacer flexibility, is localized primarily near the hydrophobic core and its partial presentation on the surface occurs only in nanoparticles with higher ligand densities. However, an increase in biotin density leads to its clustering. In turn, ligand clustering diminishes the stealth properties of the shell and targeting efficiency. Based on nanoparticle surface structures, we determined the optimal density of biotin. Experimental studies reported in the literature confirm these conclusions. We also suggest design tips to achieve the preferred biotin presentation. Simulation results are consistent with the synchrotron SAXS profile. We believe that such studies will contribute to a better understanding of nano-bio interactions towards the rational design of efficient drug delivery systems.

CRISPR Deletion of miR-27 Impacts Recombinant Protein Production in CHO Cells.

MicroRNAs represent an interesting group of regulatory molecules with the unique ability of a single miRNA able to regulate the expression of potentially hundreds of target genes. In that regard, their utility has been demonstrated as a strategy to improve the cellular phenotypes important in the biomanufacturing of recombinant proteins. Common approaches to stably deplete miRNAs are the use of sponge decoy transcripts or shRNA inhibitors, both of which require the introduction and expression of extra genetic material in the cell. As an alternative, we implemented the CRISPR/Cas9 system in our laboratory to generate CHO cells which lack the expression of a specific miRNA for the purpose of functional studies. To implement the system, miR-27a/b was chosen as it has been shown to be upregulated during hypothermic conditions and therefore may be involved in influencing CHO cell growth and recombinant protein productivity. In this chapter, we present a protocol for targeting miRNAs in CHO cells using CRISPR/Cas9 and the analysis of the resulting phenotype, using miR-27 as an example. We show that it is possible to target miRNAs in CHO cells and achieved ≥80% targeting efficiency. Indel analysis and TOPO-TA cloning combined with Sanger sequencing showed a range of different indels. Furthermore, it was possible to identify clones with no detectable expression of mature miR-27b. Depletion of miR-27b led to improved viability in late stages of batch and fed-batch cultures, making it a potentially interesting target to improve bioprocess performance of CHO cells.

Pharmacological inhibition of MYC to mitigate chemoresistance in preclinical models of squamous cell carcinoma.

Rationale: Cisplatin-based chemotherapy is the first-line treatment for late-stage head and neck squamous cell carcinoma (HNSCC). However, resistance to cisplatin has become a major obstacle for effective therapy. Cancer stem cells (CSCs) are critical for tumor initiation, growth, metastasis, and chemoresistance. How to effectively eliminate CSCs and overcome chemoresistance remains a key challenge. Herein, we confirmed that MYC plays critical roles in chemoresistance, and explored targeting MYC to overcome cisplatin resistance in preclinical models. Methods: The roles of MYC in HNSCC cisplatin resistance and cancer stemness were tested in vitro and in vivo. The combined therapeutic efficiency of MYC targeting using the small molecule MYC inhibitor MYCi975 and cisplatin was assessed in a 4‑nitroquinoline 1-oxide-induced model and in a patient-derived xenograft model. Results: MYC was highly-expressed in cisplatin-resistant HNSCC. Targeting MYC using MYCi975 eliminated CSCs, prevented metastasis, and overcame cisplatin resistance. MYCi975 also induced tumor cell-intrinsic immune responses, and promoted CD8+ T cell infiltration. Mechanistically, MYCi975 induced the DNA damage response and activated the cGAS-STING-IRF3 signaling pathway to increase CD8+ T cell-recruiting chemokines. Conclusions: Our findings suggested that targeting MYC might eliminate CSCs, prevent metastasis, and activate antitumor immunity to overcome cisplatin resistance in HNSCC.

Orally Administrated Hydrogel Harnessing Intratumoral Microbiome and Microbiota-Related Immune Responses for Potentiated Colorectal Cancer Treatment.

The intestinal and intratumoral microbiota are closely associated with tumor progression and response to antitumor treatments. The antibacterial or tumor microenvironment (TME)-modulating approaches have been shown to markedly improve antitumor efficacy, strategies focused on normalizing the microbial environment are rarely reported. Here, we reported the development of an orally administered inulin-based hydrogel with colon-targeting and retention effects, containing hollow MnO2 nanocarrier loaded with the chemotherapeutic drug Oxa (Oxa@HMI). On the one hand, beneficial bacteria in the colon specifically metabolized Oxa@HMI, resulting in the degradation of inulin and the generation of short-chain fatty acids (SCFAs). These SCFAs play a crucial role in modulating microbiota and stimulating immune responses. On the other hand, the hydrogel matrix underwent colon microbiota-specific degradation, enabling the targeted release of Oxa and production of reactive oxygen species in the acidic TME. In this study, we have established, for the first time, a microbiota-targeted drug delivery system Oxa@HMI that exhibited high efficiency in colorectal cancer targeting and colon retention. Oxa@HMI promoted chemotherapy efficiency and activated antitumor immune responses by intervening in the microbial environment within the tumor tissue, providing a crucial clinical approach for the treatment of colorectal cancer that susceptible to microbial invasion.

Regulation of neuroinflammation in Alzheimer's disease via nanoparticle-loaded phytocompounds with anti-inflammatory and autophagy-inducing properties.

Alzheimer's disease (AD) is characterized by neuroinflammation linked to amyloid β (Aβ) aggregation and phosphorylated tau (τ) protein in neurofibrillary tangles (NFTs). Key elements in Aβ production and NFT assembly, like γ-secretase and p38 mitogen-activated protein kinase (p38MAPK), contribute to neuroinflammation. In addition, impaired proteosomal and autophagic pathways increase Aβ and τ aggregation, leading to neuronal damage. Conventional neuroinflammation drugs have limitations due to unidirectional therapeutic approaches and challenges in crossing the Blood-Brain Barrier (BBB). Clinical trials for non-steroidal anti-inflammatory drugs (NSAIDs) and other therapeutics remain uncertain. Novel strategies addressing the complex pathogenesis and BBB translocation are needed to effectively tackle AD-related neuroinflammation. The current scenario demands for a much-sophisticated theranostic measures which could be achieved via customized engineering and designing of novel nanotherapeutics. As, these therapeutics functions as a double edge sword, having the efficiency of unambiguous targeting, multiple drug delivery and ability to cross BBB proficiently. Inclusion criteria involve selecting recent, English-language studies from the past decade (2013-2023) that explore the regulation of neuroinflammation in neuroinflammation, Alzheimer's disease, amyloid β, tau protein, nanoparticles, autophagy, and phytocompounds. Various study types, including clinical trials, experiments, and reviews, were considered. Exclusion criteria comprised non-relevant publication types, studies unrelated to Alzheimer's disease or phytocompounds, those with methodological flaws, duplicates, and studies with inaccessible data. In this study, polymeric nanoparticles loaded with specific phytocompounds and coated with an antibody targeting the transferrin receptor (anti-TfR) present on BBB. Thereafter, the engineered nanoparticles with the ability to efficiently traverse the BBB and interact with target molecules within the brain, could induce autophagy, a cellular process crucial for neuronal health, and exhibit potent anti-inflammatory effects. Henceforth, the proposed combination of desired phytocompounds, polymeric nanoparticles, and anti-TfR coating presents a promising approach for targeted drug delivery to the brain, with potential implications in neuroinflammatory conditions such as Alzheimer's disease.