Highly BBB-permeable nanomedicine reverses neuroapoptosis and neuroinflammation to treat Alzheimer's disease.

The prevalence of Alzheimer's disease (AD) is increasing globally due to population aging. However, effective clinical treatment strategies for AD still remain elusive. The mechanisms underlying AD onset and the interplay between its pathological factors have so far been unclear. Evidence indicates that AD progression is ultimately driven by neuronal loss, which in turn is caused by neuroapoptosis and neuroinflammation. Therefore, the inhibition of neuroapoptosis and neuroinflammation could be a useful anti-AD strategy. Nonetheless, the delivery of active drug agents into the brain parenchyma is hindered by the blood-brain barrier (BBB). To address this challenge, we fabricated a black phosphorus nanosheet (BP)-based methylene blue (MB) delivery system (BP-MB) for AD therapy. After confirming the successful preparation of BP-MB, we proved that its BBB-crossing ability was enhanced under near-infrared light irradiation. In vitro pharmacodynamics analysis revealed that BP and MB could synergistically scavenge excessive reactive oxygen species (ROS) in okadaic acid (OA)-treated PC12 cells and lipopolysaccharide (LPS)-treated BV2 cells, thus efficiently reversing neuroapoptosis and neuroinflammation. To study in vivo pharmacodynamics, we established a mouse model of AD mice, and behavioral tests confirmed that BP-MB treatment could successfully improve cognitive function in these animals. Notably, the results of pathological evaluation were consistent with those of the in vitro assays. The findings demonstrated that BP-MB could scavenge excessive ROS and inhibit Tau hyperphosphorylation, thereby alleviating downstream neuroapoptosis and regulating the polarization of microglia from the pro-inflammatory M1 phenotype to the anti-inflammatory M2 phenotype. Overall, this study highlights the therapeutic potential of a smart nanomedicine with the capability of reversing neuroapoptosis and neuroinflammation for AD treatment.

Theoretical basis, state and challenges of living cell-based drug delivery systems.

The therapeutic efficacy of drugs is determined, to a certain extent, by the efficiency of drug delivery. The low efficiency of drug delivery systems (DDSs) is frequently associated with serious toxic side effects and can even prove fatal in certain cases. With the rapid development of technology, drug delivery has evolved from using traditional frameworks to using nano DDSs (NDDSs), endogenous biomaterials DDSs (EBDDSs), and living cell DDSs (LCDDSs). LCDDSs are receiving widespread attention from researchers at present owing to the unique advantages of living cells in targeted drug delivery, including their excellent biocompatibility properties, low immunogenicity, unique biological properties and functions, and role in the treatment of diseases. However, the theoretical basis and techniques involved in the application of LCDDSs have not been extensively summarized to date. Therefore, this review comprehensively summarizes the properties and applications of living cells, elaborates the various drug loading approaches and controlled drug release, and discusses the results of clinical trials. The review also discusses the current shortcomings and prospects for the future development of LCDDSs, which will serve as highly valuable insights for the development and clinical transformation of LCDDSs in the future.

Nanodrug Delivery Systems for Myasthenia Gravis: Advances and Perspectives.

Myasthenia gravis (MG) is a rare chronic autoimmune disease caused by the production of autoantibodies against the postsynaptic membrane receptors present at the neuromuscular junction. This condition is characterized by fatigue and muscle weakness, including diplopia, ptosis, and systemic impairment. Emerging evidence suggests that in addition to immune dysregulation, the pathogenesis of MG may involve mitochondrial damage and ferroptosis. Mitochondria are the primary site of energy production, and the reactive oxygen species (ROS) generated due to mitochondrial dysfunction can induce ferroptosis. Nanomedicines have been extensively employed to treat various disorders due to their modifiability and good biocompatibility, but their application in MG management has been rather limited. Nevertheless, nanodrug delivery systems that carry immunomodulatory agents, anti-oxidants, or ferroptosis inhibitors could be effective for the treatment of MG. Therefore, this review focuses on various nanoplatforms aimed at attenuating immune dysregulation, restoring mitochondrial function, and inhibiting ferroptosis that could potentially serve as promising agents for targeted MG therapy.

Astragaloside IV protects against autoimmune myasthenia gravis in rats via regulation of mitophagy and apoptosis.

Astragaloside IV (AS­IV) has various pharmacological effects, including antioxidant and immunoregulatory properties, which can improve myasthenia gravis (MG) symptoms. However, the potential mechanism underlying the effects of AS­IV on MG remains to be elucidated. The present study aimed to investigate whether AS­IV has a therapeutic effect on MG and its potential mechanism of action. By subcutaneously immunizing rats with R97­116 peptide, an experimental autoimmune (EA) MG rat model was established. AS­IV (40 or 80 mg/kg/day) treatment was then applied for 28 days after modeling. The results demonstrated that AS­IV significantly ameliorated the weight loss, Lennon score and pathological changes in the gastrocnemius muscle of EAMG rats compared with the model group. Additionally, the levels of acetylcholine receptor antibody (AChR­Ab) were significantly decreased, whereas mitochondrial function [ATPase and cytochrome c (Cyt­C) oxidase activities] and ultrastructure were improved in the AS­IV treated rats. Moreover, the mRNA and protein expression levels of phosphatase and tensin homolog­induced putative kinase 1, Parkin, LC3II and Bcl­2, key signaling molecules for mitophagy and apoptosis, were upregulated, whereas the mRNA and protein expression levels of p62, Cyt­C, Bax, caspase 3 and caspase 9 were downregulated following AS­IV intervention. In conclusion, AS­IV may protect against EAMG in a rat model by modulating mitophagy and apoptosis. These findings indicated the potential mechanism underlying the effects of AS­IV on MG and provided novel insights into treatment strategies for MG.

Lymph node targeting strategy using a hydrogel sustained-release system to load effector memory T cells improves the anti-tumor efficacy of anti-PD-1.

Communication between tumors and lymph nodes carries substantial significance for antitumor immunotherapy. Remodeling the immune microenvironment of tumor-draining lymph nodes (TdLN) plays a key role in enhancing the anti-tumor ability of immunotherapy. In this study, we constructed a biomimetic artificial lymph node structure composed of F127 hydrogel loading effector memory T (TEM) cells and PD-1 inhibitors (aPD-1). The biomimetic lymph nodes facilitate the delivery of TEM cells and aPD-1 to the TdLN and the tumor immune microenvironment, thus realizing effective and sustained anti-tumor immunotherapy. Exploiting their unique gel-forming and degradation properties, the cold tumors were speedily transformed into hot tumors via TEM cell supplementation. Meanwhile, the efficacy of aPD-1 was markedly elevated compared with conventional drug delivery methods. Our finding suggested that the development of F127@TEM@aPD-1 holds promising potential as a future novel clinical drug delivery technique. STATEMENT OF SIGNIFICANCE: F127@TEM@aPD-1 show unique advantages in cancer treatment. When injected subcutaneously, F127@TEM@aPD-1 can continuously supplement TEM cells and aPD-1 to tumor draining lymph nodes (TdLN) and the tumor microenvironment, not only improving the efficacy of ICB therapy through slow release, but also exhibiting dual regulatory effects on the tumor and TdLN.

Brain-Targeted Black Phosphorus-Based Nanotherapeutic Platform for Enhanced Hypericin Delivery in Depression.

Depression is a significant global health concern that remains inadequately treated due to the limited effectiveness of conventional drug therapies. One potential therapeutic agent, hypericin (HYP), is identified as an effective natural antidepressant. However, its poor water solubility, low bioavailability, and limited ability to penetrate the brain parenchyma have hindered its clinical application. To address these shortcomings and enhance the therapeutic efficacy of HYP, it is loaded onto black phosphorus nanosheets (BP) modified with the neural cell-targeting peptide RVG29 to synthesize a nanoplatform named BP-RVG29@HYP (BRH). This platform served as a nanocarrier for HYP and integrated the advantages of BP with advanced delivery methods and precise targeting strategies. Under the influence of 808 nm near-infrared irradiation (NIR), BRH effectively traversed an in vitro BBB model. In vivo experiments validated these findings, demonstrating that treatment with BRH significantly alleviated depressive-like behaviors and oxidative stress in mice. Importantly, BRH exhibited an excellent safety profile, causing minimal adverse effects, which highlighted its potential as a promising therapeutic agent. In brief, this novel nanocarrier holds great promise in the development of antidepressant drugs and can create new avenues for the treatment of depression.

Developing liver-targeted naringenin nanoparticles for breast cancer endocrine therapy by promoting estrogen metabolism.

Endocrine therapy is standard for hormone receptor-positive (HR+) breast cancer treatment. However, current strategies targeting estrogen signaling pay little attention to estradiol metabolism in the liver and is usually challenged by treatment failure. In a previous study, we demonstrated that the natural compound naringenin (NAR) inhibited HR+ breast cancer growth by activating estrogen sulfotransferase (EST) expression in the liver. Nevertheless, the poor water solubility, low bio-barrier permeability, and non-specific distribution limited its clinical application, particularly for oral administration. Here, a novel nano endocrine drug NAR-cell penetrating peptide-galactose nanoparticles (NCG) is reported. We demonstrated that NCG presented specific liver targeting and increased intestinal barrier permeability in both cell and zebrafish xenotransplantation models. Furthermore, NCG showed liver targeting and enterohepatic circulation in mouse breast cancer xenografts following oral administration. Notably, the cancer inhibition efficacy of NCG was superior to that of both NAR and the positive control tamoxifen, and was accompanied by increased hepatic EST expression and reduced estradiol levels in the liver, blood, and tumor tissue. Moreover, few side effects were observed after NCG treatment. Our findings reveal NCG as a promising candidate for endocrine therapy and highlight hepatic EST targeting as a novel therapeutic strategy for HR+ breast cancer.

Customized Intranasal Hydrogel Delivering Methylene Blue Ameliorates Cognitive Dysfunction against Alzheimer's Disease.

The accumulation of hyperphosphorylated tau protein aggregates is a key pathogenic event in Alzheimer's disease (AD) and induces mitochondrial dysfunction and reactive oxygen species overproduction. However, the treatment of AD remains challenging owning to the hindrance caused by the blood-brain barrier (BBB) and the complex pathology of AD. Nasal delivery represents an effective means of circumventing the BBB and delivering drugs to the brain. In this study, black phosphorus (BP) is used as a drug carrier, as well as an antioxidant, and loaded with a tau aggregation inhibitor, methylene blue (MB), to obtain BP-MB. For intranasal (IN) delivery, a thermosensitive hydrogel is fabricated by cross-linking carboxymethyl chitosan and aldehyde Pluronic F127 (F127-CHO) micelles. The BP-MB nanocomposite is incorporated into the hydrogel to obtain BP-MB@Gel. BP-MB@Gel could be injected intranasally, providing high nasal mucosal retention and controlled drug release. After IN administration, BP-MB is continuously released and delivered to the brain, exerting synergistic therapeutic effects by suppressing tau neuropathology, restoring mitochondrial function, and alleviating neuroinflammation, thus inducing cognitive improvements in mouse models of AD. These findings highlight a potential strategy for brain-targeted drug delivery in the management of the complex pathologies of AD.

Plant-Derived Vesicles: A New Era for Anti-Cancer Drug Delivery and Cancer Treatment.

Lipid-structured vesicles have been applied for drug delivery system for over 50 years. Based on their origin, lipid-structured vesicles are divided into two main categories, namely synthetic lipid vesicles (SLNVEs) and vesicles of mammalian origin (MDVEs). Although SLNVEs can stably transport anti-cancer drugs, their biocompatibility is poor and degradation of exogenous substances is a potential risk. Unlike SLNVEs, MDVEs have excellent biocompatibility but are limited by a lack of stability and a risk of contamination by dangerous pathogens from donor cells. Since the first discovery of plant-derived vesicles (PDVEs) in carrot cell supernatants in 1967, emerging evidence has shown that PDVEs integrate the advantages of both SLNVEs and MDVEs. Notably, 55 years of dedicated research has indicated that PDVEs are an ideal candidate vesicle for drug preparation, transport, and disease treatment. The current review systematically focuses on the role of PDVEs in cancer therapy and in particular compares the properties of PDVEs with those of conventional lipid vesicles, summarizes the preparation methods and quality control of PDVEs, and discusses the application of PDVEs in delivering anti-cancer drugs and their underlying molecular mechanisms for cancer therapy. Finally, the challenges and future perspectives of PDVEs for the development of novel therapeutic strategies against cancer are discussed.

Extracellular vesicles: a rising star for therapeutics and drug delivery.

Extracellular vesicles (EVs) are nano-sized, natural, cell-derived vesicles that contain the same nucleic acids, proteins, and lipids as their source cells. Thus, they can serve as natural carriers for therapeutic agents and drugs, and have many advantages over conventional nanocarriers, including their low immunogenicity, good biocompatibility, natural blood-brain barrier penetration, and capacity for gene delivery. This review first introduces the classification of EVs and then discusses several currently popular methods for isolating and purifying EVs, EVs-mediated drug delivery, and the functionalization of EVs as carriers. Thereby, it provides new avenues for the development of EVs-based therapeutic strategies in different fields of medicine. Finally, it highlights some challenges and future perspectives with regard to the clinical application of EVs.

Innovative Strategies for Hair Regrowth and Skin Visualization.

Today, about 50% of men and 15-30% of women are estimated to face hair-related problems, which create a significant psychological burden. Conventional treatments, including drug therapy and transplantation, remain the main strategies for the clinical management of these problems. However, these treatments are hindered by challenges such as drug-induced adverse effects and poor drug penetration due to the skin's barrier. Therefore, various efforts have been undertaken to enhance drug permeation based on the mechanisms of hair regrowth. Notably, understanding the delivery and diffusion of topically administered drugs is essential in hair loss research. This review focuses on the advancement of transdermal strategies for hair regrowth, particularly those involving external stimulation and regeneration (topical administration) as well as microneedles (transdermal delivery). Furthermore, it also describes the natural products that have become alternative agents to prevent hair loss. In addition, given that skin visualization is necessary for hair regrowth as it provides information on drug localization within the skin's structure, this review also discusses skin visualization strategies. Finally, it details the relevant patents and clinical trials in these areas. Together, this review highlights the innovative strategies for skin visualization and hair regrowth, aiming to provide novel ideas to researchers studying hair regrowth in the future.

"Swiss Army Knife" black phosphorus-based nanodelivery platform for synergistic antiparkinsonian therapy via remodeling the brain microenvironment.

The combination of excessive reactive oxygen species (ROS) levels, neuroinflammation, and pathogenic protein aggregation disrupt the homeostasis of brain microenvironment, creating conditions conducive to the progression of Parkinson's disease (PD). Restoring homeostasis by remodeling the brain microenvironment could reverse this complex pathological progression. However, treatment strategies that can induce this effect are currently unavailable. Herein, we developed a "Swiss Army Knife" nanodelivery platform consisting of matrine (MT) and polyethylene glycol-modified black phosphorus nanosheets (BP) that enables PD treatment by restoring brain microenvironment homeostasis. Under NIR irradiation, the photothermal effect induced by BP allowed the nanomedicine to cross the blood-brain barrier (BBB) and entered the brain parenchyma. In PD brains, the biological effects of BP and MT resulted in the removal of excess ROS, effective reduction of neuroinflammation, decreased aggregation of pathogenic proteins, and improved neurotransmitter delivery, eventually restoring dopamine levels in the striatum. This study demonstrated the effective capacity of a BP-based nanodelivery platform to enter the brain parenchyma and trigger multiple neuropathological changes in PD brains. The platform serves as a safe and effective anti-PD nanomedicine with immense clinical potential.

Biomimetic manganese-based theranostic nanoplatform for cancer multimodal imaging and twofold immunotherapy.

The limited clinical response and serious side effect have been challenging in cancer immunotherapy resulting from immunosuppressive tumor microenvironment (TME) and inferior drug targeting. Herein, an active targeting TME nanoplatform capable of revising the immunosuppressive TME microenvironment is designed. Briefly, gold nanorods (GNRs) are covered with silica dioxide (SiO2) and then coated manganese dioxide (MnO2) to obtain GNRs@SiO2@MnO2 (GSM). Myeloid-derived suppressor cells (MDSCs) membrane is further camouflaged on the surface of GSM to obtain GNRs@SiO2@MnO2@MDSCs (GSMM). In this system, GSMM inherits active targeting TME capacity of MDSCs. The localized surface plasmon resonance of GNRs is developed in near-infrared II window by MnO2 layer coating, realizing NIR-II window photothermal imaging and photoacoustic imaging of GSMM. Based on the release of Mn2+ in acidic TME, GSMM can be also used for magnetic resonance imaging. In cancer cells, Mn2+ catalyzes H2O2 into ·OH for (chemodynamic therapy) CDT leading to activate cGAS-STING, but also directly acts on STING inducing secretion of type I interferons, pro-inflammatory cytokines and chemokines. Additionally, photothermal therapy and CDT-mediated immunogenic cell death of tumor cells can further enhance anti-tumor immunity via exposure of CRT, HMGB1 and ATP. In summary, our nanoplatform realizes multimodal cancer imaging and dual immunotherapy.

Multifunctional Graphene Oxide Nanodelivery Platform for Breast Cancer Treatment.

Background: Breast cancer (BC) has the highest global prevalence among all malignancies in women and the second highest prevalence in the overall population. Paclitaxel (PTX), a tricyclic diterpenoid, is effective against BC. However, its poor solubility in water and the allergenicity of its dissolution medium limited its clinical application. Methods: In this work, we established a multifunctional graphene oxide (GO) tumor-targeting drug delivery system using nanosized graphene oxide (nGO) modified with D-tocopherol polyethylene glycol succinate (TPGS) and arginine-glycine-aspartic acid (RGD) for PTX loading. Results: The obtained RGD-TPGS-nGO-PTX was 310.20±19.86 nm in size; the polydispersity index (PDI) and zeta potential were 0.21±0.020 and -23.42 mV, respectively. The mean drug loading capacity of RGD-TPGS-nGO-PTX was 48.78%. RGD-TPGS-nGO-PTX showed satisfactory biocompatibility and biosafety and had no significant toxic effects on zebrafish embryos. Importantly, it exerted excellent cytotoxicity against MDA-MB-231 cells, reversed multi-drug resistance (MDR) in MCF-7/ADR cells, and showed significant anti-tumor efficacy in tumor-bearing nude mice. Conclusion: These findings strongly suggested that the multifunctional GO tumor-targeting drug delivery system RGD-TPGS-nGO-PTX could be used in clinical settings to improve PTX delivery, reverse MDR and increase the therapeutic efficacy of BC treatment.

Robust boron nanoplatform provokes potent tumoricidal activities via inhibiting heat shock protein.

Near-infrared (NIR)-light-triggered photothermal therapy (PTT) is a promising treatment for breast cancer. However, its therapeutic efficiency is often compromised due to the heat-induced up-regulation of heat shock proteins, which confer photothermal resistance. To solve this urgent problem, PEGylated two-dimensional boron nanosheets (B-PEG)-which allow both multimodal imaging and photothermal conversion-were loaded with gambogic acid (GA), which can inhibit heat shock protein 90 (Hsp90). Experimental findings indicated that this combination of B-PEG and GA could serve as an integrated drug delivery system for cancer diagnosis and treatment. It could be used to administer mild PTT as well as chemotherapy for breast cancer, provide improved anti-tumor effects, and reduce the toxicity of PTT, all while inhibiting breast cancer growth. This drug delivery system could offer a novel tool for administering chemotherapy combined with PTT while avoiding the adverse effects of traditional PTT.

Brain-Targeted Biomimetic Nanodecoys with Neuroprotective Effects for Precise Therapy of Parkinson's Disease.

Parkinson's disease (PD) is a neurodegenerative disorder characterized by the gradual loss of dopaminergic neurons in the substantia nigra and the accumulation of α-synuclein aggregates called Lewy bodies. Here, nanodecoys were designed from a rabies virus polypeptide with a 29 amino acid (RVG29)-modified red blood cell membrane (RBCm) to encapsulate curcumin nanocrystals (Cur-NCs), which could effectively protect dopaminergic neurons. The RVG29-RBCm/Cur-NCs nanodecoys effectively escaped from reticuloendothelial system (RES) uptake, enabled prolonged blood circulation, and enhanced blood-brain barrier (BBB) crossing after systemic administration. Cur-NCs loaded inside the nanodecoys exhibited the recovery of dopamine levels, inhibition of α-synuclein aggregation, and reversal of mitochondrial dysfunction in PD mice. These findings indicate the promising potential of biomimetic nanodecoys in treating PD and other neurodegenerative diseases.

Efficient Sustained-Release Nanoparticle Delivery System Protects Nigral Neurons in a Toxin Model of Parkinson's Disease.

Parkinson's disease (PD) is a serious neurodegenerative disease wherein the progressive destruction of dopaminergic neurons results in a series of related movement disorders. Effective oral delivery of anti-Parkinson's drugs is challenging owing to the blood-brain barrier (BBB) and the limited plasma exposure. However, polymeric nanoparticles possess great potential to enhance oral bioavailability, thus improving drug accumulation within the brain. In this work, biodegradable poly(ethylene glycol)-b-poly(trimethylene carbonate) (PEG-PTMC) nanoparticles (PPNPs) were developed to deliver Ginkgolide B (GB) as a potent treatment for PD, aiming to enhance its accumulation within both the blood and the brain. The resultant GB-PPNPs were able to facilitate sustained GB release for 48 h and to protect against 1-methyl-4-phenylpyridine (MPP+)-induced neuronal cytotoxicity without causing any toxic damage. Subsequent pharmacokinetic studies revealed that GB-PPNPs accumulated at significantly higher concentrations in the plasma and brain relative to free GB. Oral GB-PPNP treatment was also linked to desirable outcomes in an animal model of PD, as evidenced by improvements in locomotor activity, levels of dopamine and its metabolites, and tyrosine hydroxylase activity. Together, these data suggest that PPNPs may represent promising tools for the effective remediation of PD and other central nervous system disorders.

Ultrasmall Coordination Polymers for Alleviating ROS-Mediated Inflammatory and Realizing Neuroprotection against Parkinson's Disease.

Parkinson's disease (PD) is the second most common neurodegenerative disease globally, and there is currently no effective treatment for this condition. Excessive accumulation of reactive oxygen species (ROS) and neuroinflammation are major contributors to PD pathogenesis. Herein, ultrasmall nanoscale coordination polymers (NCPs) coordinated by ferric ions and natural product curcumin (Cur) were exploited, showing efficient neuroprotection by scavenging excessive radicals and suppressing neuroinflammation. In a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced mouse PD model, such ultrasmall Fe-Cur NCPs with prolonged blood circulation and BBB traversing capability could effectively alleviate oxidative stress, mitochondrial dysfunction, and inflammatory condition in the midbrain and striatum to reduce PD symptoms. Thus, this study puts forth a unique type of therapeutics-based NCPs that could be used for safe and efficient treatment of PD with potential in clinical translation.

Nanobiotechnology: Applications in Chronic Wound Healing.

Wounds occur when skin integrity is broken and the skin is damaged. With progressive changes in the disease spectrum, the acute wounds caused by mechanical trauma have been become less common, while chronic wounds triggered with aging, diabetes and infection have become more frequent. Chronic wounds now affect more than 6 million people in the United States, amounting to 10 billion dollars in annual expenditure. However, the treatment of chronic wounds is associated with numerous challenges. Traditional remedies for chronic wounds include skin grafting, flap transplantation, negative-pressure wound therapy, and gauze dressing, all of which can cause tissue damage or activity limitations. Nanobiotechnology - which comprises a diverse array of technologies derived from engineering, chemistry, and biology - is now being applied in biomedical practice. Here, we review the design, application, and clinical trials for nanotechnology-based therapies for chronic wound healing, highlighting the clinical potential of nanobiotechnology in such treatments. By summarizing previous nanobiotechnology studies, we lay the foundation for future wound care via a nanotech-based multifunctional smart system.