Microglia usually phagocytose excessive α-synuclein (α-syn) aggregates and turn into diseased analogues in Parkinson's disease (PD), which can present α-syn-associated antigens, secrete cytokines and chemokines to recruit peripheral immune cells, and form strong immune crosstalk to aggravate PD progression. Hence, targeting the diseased microglia and inhibiting their immune crosstalk emerge as promising strategies for PD therapy. Herein, we reprogram the diseased microglia to efficiently degrade α-syn aggregates and neutralize neuroinflammatory factors to reduce the detrimental immune crosstalk and enhance therapeutic efficacy using rationally designed core-shell IHM nanoparticles, which consist of a ligustilide-functionalized Cu2-xSe nanoparticle (CSL NP) core and a hybrid cell membrane shell. The CSL NPs can redress the diseased microglia to reduce over-presented antigens by dual roles of reducing microglial RAGE-mediated phagocytosis of α-syn aggregates and increasing the microglial mature cathepsin D (m-CTSD) to efficiently degrade α-syn aggregates. The hybrid cell membrane shell is formed by a MES23.5 cell membrane (MCM) and IFN-γ-treated RAW264.7 cell membrane (IRCM). It can not only target diseased microglia by the specific interactions between VCAM-1 on the MCM and α4β1 integrin on the microglial membrane but also absorb and reduce the secretion of neuroinflammatory factors by diseased microglia through upregulated neuroinflammatory cytokine receptors such as IL1R1, TNFR1, and CCR2 on the surface of IRCM. The biomimetic core-shell IHM nanoparticles can be effectively delivered into the brain via meningeal lymphatic vessels to modulate the diseased microglia for boosting PD therapy. Our study demonstrates the promise of targeting diseased microglia to reduce their immune crosstalk in the treatment of PD and other neurodegenerative diseases.

The patch clamp technique is a fundamental tool for investigating ion channel dynamics and electrophysiological properties. This study proposes the first artificial intelligence framework for characterizing multiple ion channel kinetics of whole-cell recordings. The framework integrates machine learning for anomaly detection and deep learning for multi-class classification. The anomaly detection excludes recordings that are incompatible with ion channel behavior. The multi-class classification combined a 1D convolutional neural network, bidirectional long short-term memory, and an attention mechanism to capture the spatiotemporal patterns of the recordings. The framework achieves an accuracy of 97.58% in classifying 124 test datasets into six categories based on ion channel kinetics. The utility of the novel framework is demonstrated in two applications: Alzheimer's disease drug screening and nanomatrix-induced neuronal differentiation. In drug screening, the framework illustrates the inhibitory effects of memantine on endogenous channels, and antagonistic interactions among potassium, magnesium, and calcium ion channels. For nanomatrix-induced differentiation, the classifier indicates the effects of differentiation conditions on sodium and potassium channels associated with action potentials, validating the functional properties of differentiated neurons for Parkinson's disease treatment. The proposed framework is promising for enhancing the efficiency and accuracy of ion channel kinetics analysis in electrophysiological research.

The complex pathology of Parkinson's disease (PD) requires comprehensive understanding and multi-pronged interventions for communication between nerve cells. Despite new developments in nanotechnology in the treatment of PD, in-depth exploration of their biological effects, in particular, the specific mechanisms of inflammation inhibition are lacking. Herein, using the stable cascade catalysis channel formed by polydopamine (PDA), imidazole groups, and Cu ions, a microgel system comprising functional monomers [superoxide dismutase (SOD) with double bonds, PDA, 2-methacryloyloxy ethyl phosphorylcholine (MPC), and Cu ions] is proposed for managing PD. The microgel can be efficiently delivered to the brain aided by MPC, after which a multi-level regulatory strategy targeting neurons and microglia can be initiated. The catalytic activity cascade elicited by SOD and Cu ions can regulate the anti-inflammatory phenotypic transformation of microglia by relieving oxidative stress. Meanwhile, the dopamine (DA) released from PDA can facilitate DA storage and neurogenesis, inhibiting CX3CL1 release and the CX3CR1 receptor on microglia and further regulating the CX3CL1/CX3CR1-NF-κB-NLRP3 signaling pathway in microglia to inhibit neuroinflammation. Therefore, the proposed microgel delivery system with functional monomers represents a promising therapeutic strategy for managing neuroinflammation and promoting neurogenesis in PD by intervening chemokine axis-mediated communication between neurons and microglia.

The dynamic equilibrium between acetylation and deacetylation is vital for cellular homeostasis. Parkinson's disease (PD), a neurodegenerative disorder marked by α-synuclein (α-syn) accumulation and dopaminergic neuron loss in the substantia nigra, is associated with a disruption of this balance. Therefore, correcting this imbalance with histone deacetylase (HDAC) inhibitors represents a promising treatment strategy for PD. CAY10603 (CAY) is a potent and selective HDAC6 inhibitor. However, because of its poor water solubility and short biological half-life, it faces clinical limitations. Herein, we engineered lactoferrin-decorated CAY-loaded poly(lactic-co-glycolic acid) nanoparticles (denoted as PLGA@CAY@Lf NPs) to effectively counter methamphetamine (Meth)-induced PD. PLGA@CAY@Lf NPs showed enhanced blood-brain barrier crossing and significant brain accumulation. Notably, CAY released from PLGA@CAY@Lf NPs restored the disrupted acetylation balance in PD, resulting in neuroprotection by reversing mitochondrial dysfunction, suppressing reactive oxygen species, and inhibiting α-syn accumulation. Additionally, PLGA@CAY@Lf NPs treatment normalized dopamine and tyrosine hydroxylase levels, reduced neuroinflammation, and improved behavioral impairments. These findings underscore the potential of PLGA@CAY@Lf NPs in treating Meth-induced PD and suggest that an innovative HDAC6-inhibitor-based strategy can be used to treat PD.

Parkinson's disease (PD) is a complex neurological condition caused due to inheritance, environment, and behavior among various other parameters. The onset, diagnosis, course of therapy, and future of PD are thoroughly examined in this comprehensive review. This review also presents insights into pathogenic mechanisms of reactive microgliosis, Lewy bodies, and their functions in the evolution of PD. It addresses interaction complexity with genetic mutations, especially in genes such as UCH-L1, parkin, and α-synuclein, which illuminates changes in the manner dopaminergic cells handle proteins and use proteases. This raises the improved outcomes and life quality for those with PD. Potential treatments for severe PD include new surgical methods like Deep Brain Stimulation (DBS). Further, exploration of non-motor manifestations, such as cognitive impairment, autonomic dysfunction, and others, is covered in this review article. These symptoms have a significant impact on patients' quality of life. Furthermore, one of the emerging therapeutic routes that are being investigated is neuroprotective medicines that aim to prevent the aggregation of α-synuclein and interventions that modify the progression of diseases. The review concludes by stressing the dynamic nature of PD research and the potential game-changing impact of precision medicines on current approaches to therapy.

Nanotechnology holds immense promise in revolutionising healthcare, offering unprecedented opportunities in diagnostics, drug delivery, cancer therapy, and combating infectious diseases. This review explores the multifaceted landscape of nanotechnology in healthcare while addressing the critical aspects of safety and environmental risks associated with its widespread application. Beginning with an introduction to the integration of nanotechnology in healthcare, we first delved into its categorisation and various materials employed, setting the stage for a comprehensive understanding of its potential. We then proceeded to elucidate the diverse healthcare applications of nanotechnology, spanning medical diagnostics, tissue engineering, targeted drug delivery, gene delivery, cancer therapy, and the development of antimicrobial agents. The discussion extended to the current situation surrounding the clinical translation and commercialisation of these cutting-edge technologies, focusing on the nanotechnology-based healthcare products that have been approved globally to date. We also discussed the safety considerations of nanomaterials, both in terms of human health and environmental impact. We presented the in vivo health risks associated with nanomaterial exposure, in relation with transport mechanisms, oxidative stress, and physical interactions. Moreover, we highlighted the environmental risks, acknowledging the potential implications on ecosystems and biodiversity. Lastly, we strived to offer insights into the current regulatory landscape governing nanotechnology in healthcare across different regions globally. By synthesising these diverse perspectives, we underscore the imperative of balancing innovation with safety and environmental stewardship, while charting a path forward for the responsible integration of nanotechnology in healthcare.

Treatment for Parkinson's disease (PD) has been impeded by inefficient treatment results and multiple membrane barriers during drug delivery. This study reports the design, synthesis, and application of microneedles (MNs) loaded with mitochondrion-targeted liposome encapsulated iron (Fe)-isolated single-atom nanozymes (Mito@Fe-ISAzyme, MFeI), called MFeI MNs, for in situ drug delivery into the brain parenchyma and efficient enrichment of drugs in lesion sites. In in vitro experiments, MFeI can scavenge reactive oxygen species (ROS) and protect the neurons via mitochondrial targeting, guaranteeing the subsequent treatment of PD. Using PD mouse models, we compared the intravenous injection of MFeI with the brain in situ administration of MFeI MNs (in situ MFeI MNs). Results showed that in situ MFeI MNs significantly improved the deep penetration of the drug into brain parenchyma, especially in the vital pathological sites such as the substantia nigra pars compacta and striatum. Importantly, ROS elimination and neuroinflammatory remission in the lesion site were observed, thereby efficiently alleviating the behavioral disorders and pathological symptoms of PD mice. Therefore, the MNs system for in situ single-atom nanozyme liposome delivery exhibits great potential in PD treatment.

Disorders of the central nervous system (CNS) which include a wide range of neurodegenerative and neurological conditions have become a serious global issue. The presence of CNS barriers poses a significant challenge to the progress of designing effective therapeutic delivery systems, limiting the effectiveness of drugs, genes, and other therapeutic agents. Natural nanocarriers present in biological systems have inspired researchers to design unique delivery systems through biomimicry. As natural resource derived delivery systems are more biocompatible, current research has been focused on the development of delivery systems inspired by bacteria, viruses, fungi, and mammalian cells. Despite their structural potential and extensive physiological function, making them an excellent choice for biomaterial engineering, the delivery of nucleic acids remains challenging due to their instability in biological systems. Similarly, the efficient delivery of genetic material within the tissues of interest remains a hurdle due to a lack of selectivity and targeting ability. Considering that gene therapies are the holy grail for intervention in diseases, including neurodegenerative disorders such as Alzheimer's disease, Parkinson's Disease, and Huntington's disease, this review centers around recent advances in bioinspired approaches to gene delivery for the prevention of CNS disorders.

With the aim to find an alternative vehicle to the most used thermosensitive hydrogels for efficient nanotechnology-based nose-to-brain delivery approach for Parkinson's disease (PD) treatment, in this work we evaluated the Dopamine (DA) and the antioxidant grape seed-derived pro-anthocyanidins (Grape Seed Extract, GSE) co-loaded solid lipid nanoparticles (SLNs) put in slight viscous dispersions (SVDs). These SVDs were prepared by dispersion in water at low concentrations of mucoadhesive polymers to which SLN pellets were added. For the purpose, we investigated two polymeric blends, namely Poloxamer/Carbopol (PF-127/Carb) and oxidized alginate/Hydroxypropylmethyl cellulose (AlgOX/HPMC). Rheological studies showed that the two fluids possess Newtonian behaviour with a viscosity slightly higher that water. The pH values of the SVDs were mainly within the normal range of nasal fluid as well as almost no osmotic effect was associated to both SVDs. All the SVDs were capable to provide DA permeation through nasal porcine mucosa. Moreover, it was found that PF-127/Carb blend possesses penetration enhancer capability better than the Alg OX/HPMC combination. Flow cytometry studies demonstrated the uptake of viscous liquids incorporating fluorescent SLNs by human nasal RPMI 2650 cell in time-dependent manner. In conclusion, the SVD formulations may be considered promising alternatives to thermosensitive hydrogels strategy. Moreover, in a broader perspective, such SVD formulations may be also hopeful for treating various neurological diseases beyond PD treatment.

Reversible protein phosphorylation, regulated by protein phosphatases, fine-tunes target protein function and plays a vital role in biological processes. Dysregulation of this process leads to aberrant post-translational modifications (PTMs) and contributes to disease development. Despite the widespread use of artificial catalysts as enzyme mimetics, their direct modulation of proteins remains largely unexplored. To address this gap and enable the reversal of aberrant PTMs for disease therapy, we present the development of artificial protein modulators (APROMs). Through atomic-level engineering of heterogeneous catalysts with asymmetric catalytic centers, these modulators bear structural similarities to protein phosphatases and exhibit remarkable ability to destabilize the bridging μ3-hydroxide. This activation of catalytic centers enables spontaneous hydrolysis of phospho-substrates, providing precise control over PTMs. Notably, APROMs, with protein phosphatase-like characteristics, catalytically reprogram the biological function of α-synuclein by directly hydrolyzing hyperphosphorylated α-synuclein. Consequently, synaptic function is reinforced in Parkinson's disease. Our findings offer a promising avenue for reprogramming protein function through de novo PTMs strategy.

A bioreducible Zn (II)-adenine multifunctional module (BS) and Tet1 peptide were used to modify low-molecular-weight PEI3.5k (polyethyleneimine with molecular weight of 3.5 kDa)into a siRNA vector Zn-PB-T with high transfection efficiency in neurons. A GSH-responsive breakable disulfide spacer was introduced into BS to realize the controlled release of siRNA from the polyplexes in cytoplasm. Zn-PB showed >90% transfection rates in multiple cell lines (3 T3, HK-2, HepG2, 293 T, HeLa, PANC-1)，and 1.8-folds higher EGFP knockdown rates than commercial Lipo2k in normal cell line 293 T and cancer cell line HepG2. And Zn-PB-T1 showed 4.7-4.9- and 8.0-8.1-folds higher transfection efficiency comparing to commercial Lipo2k and PEI25k (polyethyleneimine with molecular weight of 25 kDa) in PC12 cells respectively, 2.1-fold EGFP gene silencing efficiency (96.6% EGFP knockdown rates) superior to commercial Lipo2k in neurons. In Parkinson's model, Zn-PB-T1/SNCA-siRNA can effectively protect neurons against MPP+-induced cell death and apoptosis, increasing the cell survival rate to 84.6% and reducing the cell apoptosis rate to 10.8%. This work demonstrated the promising application prospects of the resulting efficient siRNA carriers in siRNA-mediated gene therapy of Parkinson's disease.

Nanoprecipitation, which is achieved through the diffusion and precipitation of drug molecules in blended solvent and antisolvent phases, is a classic route for constructing nanodrugs (NDs) and previously directed by diffusion-controlled theory. However, the diffusion-controlled mechanism is out of date in the recent preparation of self-delivery supramolecular NDs (SDSNDs), characterized by the construction of drug nanoparticles through supramolecular interactions in the absence of carriers and surfactants. Herein, a "reaction"-like complement, contributed from supramolecular interactions, is proposed for the preparation of naphthoquinone SDSNDs. Different from the diffusion-controlled process, the formation rate of SDSNDs via the "reaction"-like process is almost constant and highly dependent on the supramolecular interaction-determined Gibbs free energy of molecular binding. Thus, the formation rate and drug availability of SDSNDs are greatly improved by engineering the supramolecular interactions, which facilitates the preparation of SDSNDs with expected sizes, components, and therapeutic functions. As a deep understanding of supramolecular-interaction-involved nanoprecipitation, the current "reaction"-like protocol not only provides a theoretical supplement for classic nanoprecipitation but also highlights the potential of nanoprecipitation in shaping self-assembled, coassembled, and metal-ion-associated SDSNDs.

Parkinson's disease (PD), as the second most common neurodegenerative disease after Alzheimer's, has become intractable with the increasing aging global population. The exploration of nanomedicine has broadened the opportunities for developing novel neuroprotective therapies. In particular, polymetallic functional nanomaterials have been widely used in the biomedicine field in recent years, exhibiting flexible and diversified functions and controllable properties. In this study, a tri-element nanozyme (PtCuSe nanozyme) has been developed with desirable CAT- and SOD-like activities for the cascade scavenging of reactive oxygen species (ROS). In particular, the nanozyme is suitable for relieving nerve cell damage by removing reactive oxygen species in cells and mitigating the behavioral and pathological symptoms in animal models of Parkinson's disease. Therefore, this ingenious tri-element nanozyme may have potential in the treatment of Parkinson's disease and other neurodegenerative diseases.

Over time, developments in nano-biomedical research have led to the creation of a number of systems to cure serious illnesses. Tandem use of nano-theragnostics such as diagnostic and therapeutic approaches tailored to the individual disease treatment is crucial for further development in the field of biomedical advancements. Graphene has garnered attention in the recent times as a potential nanomaterial for tissue engineering and regenerative medicines owing to its biocompatibility among the several other unique properties it possesses. The zero-dimensional graphene quantum dots (GQDs) and their nitrogen-doped variant, nitrogen-doped GQDs (N-GQDs), have good biocompatibility, and optical and physicochemical properties. GQDs have been extensively researched owing to several factors such as their size, surface charge, and interactions with other molecules found in biological media. This work briefly elucidates the potential of electroactive GQDs as well as N-GQDs as neurotrophic agents. In vitro investigations employing the N2A cell line were used to evaluate the effectiveness of GQDs and N-GQDs as neurotrophic agents, wherein basic investigations such as SRB assay and neurite outgrowth assay were performed. The results inferred from immunohistochemistry followed by confocal imaging studies as well as quantitative real-time PCR (qPCR) studies corroborated those obtained from neurite outgrowth assay. We have also conducted a preliminary investigation of the pattern of gene expression for neurotrophic and gliotrophic growth factors using ex vivo neuronal and mixed glial cultures taken from the brains of postnatal day 2 mice pups. Overall, the studies indicated that GQDs and N-GQDs hold prospect as a framework for further development of neuroactive compounds for relevant central nervous system (CNS) purposes.

With research burgeoning in nanoscience and nanotechnology, there is an urgent need to develop new biological models that can simulate native structure, function, and genetic properties of tissues to evaluate the adverse or beneficial effects of nanomaterials on a host. Among the current biological models, three-dimensional (3D) organoids have developed as powerful tools in the study of nanomaterial-biology (nano-bio) interactions, since these models can overcome many of the limitations of cell and animal models. A deep understanding of organoid techniques will facilitate the development of more efficient nanomedicines and further the fields of tissue engineering and personalized medicine. Herein, we summarize the recent progress in intestinal organoids culture systems with a focus on our understanding of the nature and influencing factors of intestinal organoid growth. We also discuss biomimetic extracellular matrices (ECMs) coupled with nanotechnology. In particular, we analyze the application prospects for intestinal organoids in investigating nano-intestine interactions. By integrating nanotechnology and organoid technology, this recently developed model will fill the gaps left due to the deficiencies of traditional cell and animal models, thus accelerating both our understanding of intestine-related nanotoxicity and the development of nanomedicines.

Worldwide nanotechnology development and application have fueled many scientific advances, but technophilic expectations and technophobic demands must be counterbalanced in parallel. Some of the burning issues today are the following: (1) Where is nano today? (2) How good are the communication and investment networks between academia/research and governments? (3) Is there any spotlight application for nanotechnology? Nanomedicine is a particular arm of nanotechnology within the healthcare landscape, focused on diagnosis, treatment, and monitoring of emerging (such as coronavirus disease 2019, COVID-19) and contemporary (including diabetes, cardiovascular diseases, neurodegenerative disorders, and cancer) diseases. However, it may only represent the bright side of the coin. In fact, in the recent past, the concept of nanotoxicology has emerged to address the dark shadows of nanomedicine. The nanomedicine field requires more nanotoxicological studies to identify undesirable effects and guarantee safety. Here, we provide an overall perspective on nanomedicine and nanotoxicology as central pieces of the giant puzzle of nanotechnology. First, the impact of nanotechnology on education and research is highlighted, followed by market trends and scientific output tendencies. In the next section, the nanomedicine and nanotoxicology dilemma is addressed through the interplay of in silico, in vitro, and in vivo models with the support of omics and microfluidic approaches. Lastly, a reflection on the regulatory issues and clinical trials is provided. Finally, some conclusions and future perspectives are proposed for a clearer and safer translation of nanomedicines from the bench to the bedside.

Parkinson's disease (PD) is an age-related neurodegenerative disease, and the removal of senescent cells has been proved to be beneficial for improving age-associated pathologies in neurodegeneration disease. In this study, chiral gold nanoparticles (NPs) with different helical directions were synthesized to selectively induce the apoptosis of senescent cells under light illumination. By modifying anti-B2MG and anti-DCR2 antibodies, senescent microglia cells could be cleared by chiral NPs without damaging the activities of normal cells under illumination. Notably, l-P+ NPs exhibited about a 2-fold higher elimination efficiency than d-P- NPs for senescent microglia cells. Mechanistic studies revealed that the clearance of senescent cells was mediated by the activation of the Fas signaling pathway. The in vivo injection of chiral NPs successfully confirmed that the elimination of senescent microglia cells in the brain could further alleviate the symptoms of PD mice in which the alpha-synuclein (α-syn) in cerebrospinal fluid (CFS) decreased from 83.83 ± 4.76 ng mL-1 to 8.66 ± 1.79 ng mL-1 after two months of treatment. Our findings suggest a potential strategy to selectively eliminate senescent cells using chiral nanomaterials and offer a promising strategy for alleviating PD.