Pre-eclampsia is a major cause of maternal and fetal mortality. Low molecular weight heparin sodium (LMWH) reduced the incidence of pre-eclampsia, may be an effective treatment of pre-eclampsia. But the underlying mechanism of LMWH was unknown. To improve the molecular utilization rate, Chitosan-LMWH nanoparticles (CHsN) were purchased for the study. The prague of pregnancy Sprague-Dawley rats were injected with nitroso L-arginine methyl ester to construct a pre-eclampsia model. Trichotrophoblast cells HTR-8/SVneo were cultured under Hypoxia/reoxygenation injury (H/R) simulation conditions to construct the cell model. CHsN ameliorated the integrity of fetal membrane tissue. Administration of CHsN resulted in decreased urine protein and HB-EGF levels, accompanied by increased numbers of pups and placenta. Treatment with CHsN increased the proportion of Treg cells and decreased the proportion of Th17 cells. After treatment with CHsN, the levels of LPS, TNF-α, rank1, slp1, Foxo, NF-κB, and HIF-1α were down-regulated, while the levels of IL-2, Foxp3, and TGFβ1 were up-regulated. CRM197 reversed the effect of CHsN. The CHsN improved H/R-induced HTR-8/SVneo cells apoptosis through HB-EGF and affected CD4+T cell differentiation. CHsN ameliorated pre-eclampsia by regulating Treg/Th17 immune balance and inflammation at the maternal-fetal interface through HB-EGF. This provided a theoretical reference for relieving pre-eclampsia by CHsN.

Parkinson's disease (PD) is starting at younger ages. In order to reduce the risk of PD in young people, Rb3 is selected as an active ingredient and assembled into Rb3 nanoparticles (Rb3NPs)encapsulated microbubbles (MBs), shorted for Rb3NPs@MBs. This study uses focused ultrasound-mediated Rb3NPs@MBs to cross the blood–brain barrier and reach the brain lesions to be intervened in in order to explore the prevention of 1-methyl-4-phenyl-4-piperidinpropionate ester (MPTP)-induced PD by Rb3NPs@MBs and its related mechanisms. In the present study, Rb3NPs@MBs prevent MPTP-induced tyrosine hydroxylase (TH)-positive cell decreases, decrease TH expression, increase Park2 expression, and decrease expression of α-synaptonucleoprotein in the pars compactus nigra (SNc). It is found, in vitro study, that Rb3NPs treatment significantly reverses MPTP-induced apoptosis and death of PC12/SY5Y cells, which is commonly used mouse/ human neural cell lines. It is also found that Rb3NPs@MBs can prevent the production of reactive oxygen species (ROS) in SNc. Finally, it is found that DJ-1 expression decreases after Rb3NPs@MBs are introduced. Results suggest that the neuroprotective activity of Rb3NPs@MBs may be achieved by increasing the expression of DJ-1 and decreasing the production of ROS. Taken together, these data reveal that Rb3NPs@MBs play an important role in preventing memory deficiency in PD.

Gold nanorods and cyanine dyes are promising to be widely used in photothermal therapy due to their adjustable absorption wavelength and excellent photothermal conversion efficiency. However, it is unclear how gold nanorods differ from cyanine dyes in therapeutic effects. Nanocapsules are synthesized from hybrid silica encapsulated gold nanorods (AuNRs@YSiO2, hereafter GNR@YS). Composite nanocapsules (hereafter GNR@YS-CyN) are prepared from GNR@YS loaded with CyN to treat subcutaneous tumor. Cyanine dye (CyCl) with similar absorption to gold nanorods is also synthesized to match the existing commercial 808 nm laser. The results show that both materials have good therapeutic effect, but differ in healing scabs on skin tissue surface after tumor ablation. GNR@YS-CyN are superior to CyCl in the treatment of subcutaneous tumor. This may be the size effect of GNR@YS-CyN has permeability and retention enhancement effect at the tumor site. GNR@YS-CyN have no obvious dye diffusion phenomenon, which reduces the damage to normal tissue.

The dense stromal matrix in fibrotic tumors hinders tumor-targeted drug delivery. Tamoxifen (TMX), an estrogen receptor modulator that is clinically used for the treatment of breast cancer, is shown to reprogram the tumor microenvironment (TME) and to alleviate desmoplasia. It is investigated if TMX, administered in free and nano-formulated form, can be repurposed as a TME remodeling agent to improve tumor accumulation of nano-formulations in pancreatic ductal adenocarcinoma and triple-negative breast cancer mouse models, evaluated using clinical-stage Cy7-labeled core-crosslinked polymeric micelles (CCPM). Under control conditions, higher levels of Cy7-CCPM are found in PANC-1 tumors (16.7% ID g−1 at 48 h post i.v. injection) than in 4T1 tumors (11.0% ID g−1). In both models, free and nano-formulated TMX failed to improve CCPM delivery. These findings are congruent with the results from histopathological immunofluorescence analysis of tumor tissue, which indicate that TMX treatment does not significantly change vascularization, perfusion, macrophage infiltration, collagen density, and collagen fiber thickness. Altogether, these results demonstrate that in PANC-1 and 4T1 mouse models, TMX treatment does not contribute to beneficial TME priming and enhanced tumor-targeted drug delivery.

Oesophageal squamous carcinoma (ESCC) is one of the most lethal human malignancies worldwide, especially in China, due to its late-stage diagnosis, chemoradiotherapy resistance, and lack of appropriate therapeutic targets and corresponding therapeutic formulations. In article number 2200251, Bing Jiang and co-workers review the latest genomics, diagnostics, etiology, and therapeutic researches of ESCC to provide a comprehensive discussion and seek breakthrough on the theranostics of ESCC.

Glioblastoma (GBM) is a malignant brain tumor with a poor prognosis that easily recurs. The antiangiogenic agent bevacizumab is used to treat recurrent GBM. However, GBM treated with bevacizumab easily rebounds due to evasive mechanisms that induce resistance to treatment, such as hypoxia-inducible factor (HIF)-associated pathways. The transcription regulator HIFs are oxygen-dependent and are degraded via the ubiquitin-dependent proteasomal pathway. Therefore, it is necessary to study bevacizumab resistance with HIF-associated pathways through translational mRNA profiling. W e applied a hypoxia response element (HRE) promoter to the ribosome affinity purification (TRAP) system for hypoxia-specific translational mRNA profiling analysis. Here, w e analyzed the translatome of pseudopalisading cells in the brain samples of orthotopic mouse models using ou r hypoxia-responsive 5×HRE-TRAP system to investigate the molecular mechanism of drug resistance on pseudopalisading cells around the necrotic area induced by bevacizumab resistance. The translatomic analysis result shows that pseudopalisading cells exhibit notable enrichment of gene sets associated with neurodegenerative diseases, such as Alzheimer's disease. The outcomes of this study enhance o ur clinical relevance, meaning that the translatomic analysis result of pseudopalisading cells during bevacizumab treatment-induced resistance provides new insight into a promising approach for developing targeted therapeutics.

Mitochondrial membrane potential (ΔΨm)-targeting molecular probes play an essential role in diagnosing and treating diseases. Recently, the second near-infrared window (NIR-II, 1000–1700 nm) fluorescent imaging has been actively studied as an attractive imaging modality. However, small molecule ΔΨm-targeting NIR-II probes are rarely reported, especially for highly efficient imaging and treatment of tumors. Herein, a small molecule probe named TQPTPP is designed and synthesized by conjugation of a novel D-A type dye TQT1009 with ΔΨm-targeting molecule alkyl triphenylphosphine (TPP) through a polyethylene glycol-8 (PEG8) linker. The conventional ICG dye is also coupled with TPP through PEG8 to produce ICGTPP as a comparison. TQPTPP showed a fluorescence quantum yield of 0.041% and excellent photothermal conversion efficiency (61.4%). It can be self-assembled into nanoparticles and still preserve ΔΨm-targeting capability. Tumor imaging is further performed, and results showed a long tumor retention time of TQPTPP (maximum tumor signal on day five and signal-to-noise ratio up to nine). As a comparison, ICGTPP remained a single molecule with ΔΨm-targeting capability. But it has shorter tumor retention and lower photostability. These results suggested the novel D-A small molecule ΔΨm-targeting NIR-II probe TQPTPP provided a new tool for diagnosing and treating tumors.

Alzheimer's disease (AD) is a neurodegenerative disease and the most common cause of dementia. Although it is discovered more than 100 years ago and is the subject of many scientific studies, much is yet to be discovered about many aspects of this disease, including the precise biological changes that cause it, the best approach to its early diagnosis, and effective therapeutic interventions to slow or stop the progression. This article briefly reviews the disease progression, risk factors, and pathogenesis of the disease. In addition, the current early diagnostic and therapeutical strategies for AD are presented.

Transmural skip lesions are pathognomonic for Crohn's disease (CD). Despite advances toward CD treatment, disease recurrence remains a problem. CD requires novel therapies to modulate localized intestinal inflammation and promote intestinal epithelium healing. Human neonatal cardiac-derived mesenchymal stem cells (nMSCs) demonstrate immune cell modulation accompanied by improved cardiac function recovery in myocardial infarction models. In the established CD-like ileitis SAMP mouse model, direct skip lesion injection of nMSCs prevents ileal skip lesion growth and significantly down-regulates the pro-inflammatory milieu. Significant reduction in the percentage of skip lesion CD68+ macrophages (M1 Mφ, pro-inflammatory) accompanied by an increase of CD206+ macrophages (M2 Mφ, anti-inflammatory/pro-regenerative) is observed in skip lesions following nMSCs injection compared to non-injected and placebo controls (p < 0.05). Skip lesion size is significantly reduced along with pro-inflammatory cytokines IFN-y and TNF-α, with an increase in intestinal tissue anti-inflammatory cytokine IL-10 production. nMSCs are also retained within skip lesions 5 weeks post-treatment. nMSC administration promotes wound remodeling by modulating inflammatory immune cells and by increasing small bowel gastrointestinal transit with concomitant decreased segment gross pathology score compared to placebo control. Data from this study demonstrate that direct injection of nMSCs into ileal skip lesions attenuates inflammation and improves intestinal physiology.

The rapid advancement of nanotechnology in recent years has opened new avenues of investigation for biomedical sciences. Viral nanoparticles (VNPs) are formulated from plant viruses, mammalian viruses, or bacteriophages. Based on their structure, viruses, and synthetic carriers have been utilized to design bio-inspired nanocarriers, which serve as building blocks for innovative therapeutic applications. Scientists can chemically or genetically engineer VNPs to encompass various properties, such as enhancing their functionalization with therapeutic molecules and imaging reagents, enabling targeted delivery to specific ligands. The implementation of these novel nanocarrier platforms can revolutionize treatments for cancer, infectious diseases, and chronic illnesses. The primary goal of drug delivery systems is to localize cargo to the specific target site, increasing therapeutic benefits and minimizing off-target effects. This review critically evaluates the major virus species used as nanocarriers, their applications in therapeutics, and their advantages and disadvantages.

The use of fibrous hydrogel constructs is a promising strategy in tissue engineering because of their ability to closely mimic the anisotropic structure of biological tissues. In skeletal muscle tissue engineering, fiber alignment is considered a crucial factor for achieving muscle functions originating from the uniaxially aligned structure of myofibers; however, the fabrication process of hydrogel constructs with aligned fibers requires complex and laborious techniques. In this study, the effect of 3D-printed constructs with randomly oriented fibers on myoblast differentiation is evaluated. To this end, 3D-printable gelatin methacryloyl (GelMA) hydrogel microfibers through the mechanical fragmentation of electrospun GelMA sheets is prepared. The bulk rheological and tensile properties of the hydrogels with microfibers are stronger than those of the hydrogels without microfibers. Interestingly, when myoblast-embedded constructs are 3D-printed with and without randomly oriented GelMA hydrogel microfibers and incubated for cell differentiation, the microfibers in the constructs effectively promote myotubule-like cell formation. In addition, the uniaxial 3D printed design enables anisotropic myotubule formation. This shows that hydrogels with only fibers distributed randomly can be applied to achieve more effective artificial muscle constructs than those achieved using normal bulk hydrogels and are easier to use than aligned fibers.

Recent research offers several approaches for the advancement of manganese-based nanomaterials for its therapeutic use. The present research paper reports the development of smartly engineered casein manganese oxide nanobiomaterials (CMnNP) using manganese chloride and casein under alkaline condition at room temperature. The CMnNP are systematically characterized by various analytical techniques. The biocompatibility of these nanomaterials is observed by in vitro cell viability and in vivo hemolysis assay. The nanomaterials (CMnNP) exhibit the pro-angiogenic properties, established through various in vitro assays in endothelial cells and in vivo experiments. The interaction of manganese with different enzymes and angiogenic proteins is identified through in silico analysis that is further validated through in vitro western blot studies. This study also demonstrates the application of therapeutic angiogenesis of CMnNP for wound healing as well as hindlimb ischemia in C57BL/6J and BALB/c mouse model, respectively. The formation of redox signaling molecules (especially H2O2, O2˙−, and NO) in endothelial cells may be one of the plausible mechanisms for CMnNP-mediated angiogenesis. Considering the results, the current study offers a nanomedical perspective for the therapy of various ischemic diseases as well as wound healing where angiogenesis involves is a crucial step.

Tertiary lymphoid structure (TLS) is considered to be closely related to tumor prognosis and immune response. Therefore, it has predictable clinical significance for survival prognosis and cancer drug treatment to build TLS signature of pan-cancer. The transcriptome sequencing data of The Cancer Genome Atlas pan-cancer analysis are obtained from UCSC Xena, including 33 cancer types (N = 10 066). A 15 TLS genes-based TLSscore is constructed using the Random Forest and Cox regression analyses. Then, according to TLS signature, patients are classified into low- and high-risk groups. Then, the differences between the two groups in terms of survival prognosis, functional enrichment, immune infiltration, and drug sensitivity are further explored. On the basis of machine learning algorithm, TLS signature has satisfactory prediction performance for the prognosis of pan-cancer patients. A nomogram with high predictive performance is formulated by incorporating TLS signature and clinical features. The function enrichment analysis suggests that TLS signature may be related to the key pathways of immunotherapy for pan-cancer, and shows significant differences among groups at the immune checkpoint genes. In general, a novel TLSscore-based model is established through comprehensive analysis of TLS genes, which can accurately predict the clinical prognosis and drug sensitivity of pan-cancer.

Protein-based drug delivery systems have gained popularity due to their biocompatibility, straightforward surface modification, and potential for intrinsic therapeutic activity. Among therapeutic proteins, enzymes are particularly attractive because of their specificity, efficient reaction rates, regeneration after substrate turnover, and proven track record in the treatment of diseases ranging from cancer to inherited metabolic and lysosomal storage disorders. Herein, previous work on electrohydrodynamic jetting is expanded upon by developing a novel class of protein nanoparticles that features therapeutic enzymes. In particular, nanoparticles incorporating the antioxidant enzyme, catalase, at weight fractions as high as 50% are reported. Catalase-based synthetic protein nanoparticles (CAT-SPNPs) demonstrate sustained antioxidative activity, retain significantly enhanced enzymatic activity compared to its solute form, and overall demonstrate good structural stability. Moreover, surface functionalization of CAT-SPNPs with targeting antibodies results in ≈12.5-fold increase in uptake over unmodified control particles. Importantly, CAT-SPNPs exert protection from oxidative stress, as indicated by significant increase in viability and reduction in LDH release compared to equivalent amounts of free catalase. Taken together, the work establishes targeted enzyme-based SPNPs as a platform for enhancing the drug-like properties of therapeutic enzymes.

Diabetes is one of the most pressing healthcare challenges facing society. Dysfunctional insulin signaling causes diabetes, leading to blood glucose instability and many associated complications. While the administration of exogenous insulin is then essential for achieving glucose control, issues with dosing accuracy and timing remain. Hydrogel-based drug delivery systems have been broadly explored for controlled protein release, including for applications in long-lasting and oral insulin delivery. More recently, efforts have focused on injectable hydrogels with glucose-directed controlled release of insulin and glucagon, aiming for more autonomous and biomimetic approaches to blood glucose control. These materials typically use protein-based sensing mechanisms or glucose binding by synthetic aryl boronates for glucose-directed release. Despite advancements in this area, there remains a need for more precise timing of therapeutic availability to afford healthy blood glucose homeostasis, providing an opportunity for further research and innovation. This review summarizes the current state of hydrogel-based delivery of insulin and glucagon, with insights into the potential benefits, future directions, and challenges that must be overcome to achieve clinical impact.

Adapted oxidative phosphorylation (OXPHOS) and tricarboxylic acid (TCA) cycle activations are essential tumor microenvironments for abnormal energy consumption to acquire malignancy and drug resistance during cancer development and progression. To elucidate the molecular mechanism related to the mitochondrial metabolic dynamics and drug resistance in glioblastoma (GBM), a longitudinal GBM orthotopic mouse model with acquired resistance to bevacizumab is established. The longitudinal proteomic analysis results show that OXPHOS, TCA, and calcium signaling gene sets are enriched in the bevacizumab pre-resistance phase for preparing resistance phase. Then, the APEX system to GBM to biotinylate and purify proteins of the mitochondria matrix is applied. The organelle specific proteomic analysis shows that the pore-forming subunits of the mitochondrial calcium uniporter protein (MCU) are essential for acquiring bevacizumab resistance. Additionally, a combination effect of hypoxia and the MCU-specific inhibitor DS16570511 in vitro shows that cell growth and proliferation are reduced via inhibition of NF-κB and CEBP/β signaling pathways. In conclusion, the hypoxic tumor microenvironment induced by bevacizumab treatment affects mitochondrial metabolic dynamics, and targeting MCU is a promising therapeutic option in combination with bevacizumab in recurrent GBM.

Photothermal Therapy (PTT) has been gaining wide attention in oncological applications,. Nevertheless, its efficacy is still being questioned due to the potential deleterious thermal impact on healthy tissues. The comprehension of tissue thermal properties and their role in photothermal heat transfer is critical. In this study, we initially characterize the thermal conductivity of murine mammary gland (MG) tissues (both tumorous and normal) as a function of time post-tumor cell inoculation. Notably, the tumorous mammary glands exhibited a mean thermal conductivity of 0.41±0.013 W/(m•K), a 28% increase compared to the normal tissue (0.32±0.003 W/(m•K)). We employed a self-developed ultra-fast hot wire technique to assess the marginal temperature elevation in thin mammary gland samples. Our experimental findings suggest that the thermal conductivity escalates as the tumor advances. Employing a constant-power laser, we attribute variations in therapeutic outcomes to the synergistic effect of augmented thermal conductivity and tumoral volume. Additionally, tumor expansion leads to reduced perfusion and diminished heat diffusion, consequently moderating the temperature elevation in the mice epidermis. Importantly, our data substantiates that the early commencement of photothermal irradiation effectively stymies tumor advancement. These insights and methodological advancements could foster improved early-stage PTT by calibrating irradiation schedules contingent on meticulous thermal property assessments, thus optimizing therapeutic results.

Oral delivery of peptides is severely limited by their instability and poor absorption in the gastrointestinal tract. In contrast to coadministration strategies using medium-chain fatty acids, which have recently gained regulatory approval with low oral bioavailabilities ≤ 1% (Rybelsus and Mycapssa), efforts to clinically implement delivery systems based on nanocarriers have not been successful to date. The approved drug-delivery formulations show fairly accurate correlation between clinical results and nonrodent mammal bioavailability, including Beagle dogs for Rybelsus, indicating that Beagle dogs represent a translationally relevant model. Here, a nanocarrier formulation for the oral administration of peptide therapeutics is reported with systemic targets consisting of liposomes decorated with cyclic cell-penetrating peptides, which significantly increase oral bioavailability in translationally relevant Beagle dogs. This nanocarrier formulation is optimized using the glycopeptide vancomycin, and results in a considerable oral bioavailability of 3.9%. Further, this nanocarrier system increases the oral bioavailability of the large linear peptide therapeutic exenatide 20-fold, and consistently achieves effective plasma concentrations in Beagle dogs.

A promising approach enhancing osteosarcoma (OS) prognosis involves the combination of various techniques, such as chemo- and photodynamic therapy, delivered through nanocarriers for synergistic cell death. Among the potential candidates for improving drug accumulation at the tumor site, mesenchymal stromal cells (MSCs) exhibit a significant advantage due to their tumor-homing ability and intracellular drug retention. This study evaluates the efficacy of chemo-releasing and photoactive bimodal nanoparticles, kPCe6 NPs, delivered via MSCs. In vitro analyses show that cells internalize and retain kPCe6 NPs in a dose-dependent manner and that kPCe6-loaded cells induce massive tumor cell death in a tridimensional tumor model. Results from an in vivo orthotopic OS murine model show negligible tumor cell death upon peritumoral administration of two doses containing 106 loaded cells. To gain insight into this observation, this work investigates the role of cell dose in treatment efficacy. The results indicate that achieving a tumor reduction higher than 90% requires a substantial number of loaded cells, approximately 35% of the entire tumor mass, highlighting the criticality of the cell dose for the success of this therapeutic approach and its potential impact on clinical translation in OS patients, particularly when the number of tumor cells is limited.

Ultrasmall nanoparticles (USNs) (nanoparticles with hydrodynamic diameter <10 nm) are being widely developed pre-clinically and started to emerge in clinical trials over the last decade. Most of these USNs display the same features including short retention time in the blood, rapid renal clearance, and relie on passive targeting strategy to reach the tumor. Through this review, the development of AGuIX USNs is focused on because of their clinical usages as passively targeted USN but also because of their possible biofunctionalizations with peptides and monoclonal antibodies which are validated in various pre-clinical tumor models. As a result, the authors reviewed all the current biofunctionalization strategies that can be employed and confirmed based on a meta-analysis of the literature that biofunctionalized USNs pharmacokinetic and biodistribution profiles are dictated by the USNs and not the active targeting moiety. Additionally, it is demonstrated that such active targeting strategy improves the tumor targeting efficiency of the AGuIX USN but also increases their tumor retention time in comparison to the passively targeted AGuIX USNs, which may lead to an opportunity to reduce the number of injections/expend the therapeutic benefit of the drug product.