Glycocalyx-Mimicking Nanoparticles with Differential Organ Selectivity for Drug Delivery and Therapy.

Organ-selective drug delivery is expected to maximize the efficacy of various therapeutic modalities while minimizing their systemic toxicity. Lipid nanoparticles and polymersomes can direct the organ-selective delivery of mRNAs or gene editing machineries, but their delivery is limited to mostly liver, spleen, and lung. A platform that enables delivery to these and other target organs is urgently needed. Here, a library of glycocalyx-mimicking nanoparticles (GlyNPs) comprising five randomly combined sugar moieties is generated, and direct in vivo library screening is used to identify GlyNPs with preferential biodistribution in liver, spleen, lung, kidneys, heart, and brain. Each organ-targeting GlyNP hit show cellular tropism within the organ. Liver, kidney, and spleen-targeting GlyNP hits equipped with therapeutics effectively can alleviate the symptoms of acetaminophen-induced liver injury, cisplatin-induced kidney injury, and immune thrombocytopenia in mice, respectively. Furthermore, the differential organ targeting of GlyNP hits is influenced not by the protein corona but by the sugar moieties displayed on their surface. It is envisioned that the GlyNP-based platform may enable the organ- and cell-targeted delivery of therapeutic cargoes.

Longitudinal Magnetic Resonance Imaging with ROS-Responsive Bilirubin Nanoparticles Enables Monitoring of Nonalcoholic Steatohepatitis Progression to Cirrhosis.

Despite the vital importance of monitoring the progression of nonalcoholic fatty liver disease (NAFLD) and its progressive form, nonalcoholic steatohepatitis (NASH), an efficient imaging modality that is readily available at hospitals is currently lacking. Here, a new magnetic-resonance-imaging (MRI)-based imaging modality is presented that allows for efficient and longitudinal monitoring of NAFLD and NASH progression. The imaging modality uses manganese-ion (Mn2+)-chelated bilirubin nanoparticles (Mn@BRNPs) as a reactive-oxygen-species (ROS)-responsive MRI imaging probe. Longitudinal T1-weighted MR imaging of NASH model mice is performed after injecting Mn@BRNPs intravenously. The MR signal enhancement in the liver relative to muscle gradually increases up to 8 weeks of NASH progression, but decreases significantly as NASH progresses to the cirrhosis-like stage at weeks 10 and 12. A new dual input pseudo-three-compartment model is developed to provide information on NASH stage with a single MRI scan. It is also demonstrated that the ROS-responsive Mn@BRNPs can be used to monitor the efficacy of potential anti-NASH drugs with conventional MRI. The findings suggest that the ROS-responsive Mn@BRNPs have the potential to serve as an efficient MRI contrast for monitoring NASH progression and its transition to the cirrhosis-like stage.

Liposomal Delivery of an Immunostimulatory CpG Induces Robust Antitumor Immunity and Long-Term Immune Memory by Reprogramming Tumor-Associated Macrophages.

Tumor-associated macrophages (TAMs)-representative immune-suppressive cells in the tumor microenvironment (TME)-are known to promote tumor progression and metastasis, and thus are considered an attractive target for cancer therapy. However, current TAM-targeting strategies are insufficient to result in robust antitumor efficacy. Here, a small lipid nanoparticle encapsulating immunostimulatory CpG oligodeoxynucleotides (SLNP@CpG) is reported as a new immunotherapeutic modality that can reprogram TAMs and further bridge innate-to-adaptive immunity. It is found that SLNP@CpG treatment enhances macrophage-mediated phagocytosis of cancer cells and tumor antigen cross-presentation, and skews the polarization state of macrophages in vitro. Intratumoral injection of SLNP@CpG into an established murine E.G7-OVA tumor model significantly suppresses tumor growth and considerably prolongs survival, completely eradicating tumors in 83.3% of mice. Furthermore, tumor-free mice resist rechallenge with E.G7-OVA cancer cells through induction of immunological memory and long-term antitumor immunity. SLNP@CpG even exerts antitumor efficacy in an aggressive B16-F10 melanoma model by remodeling TME toward immune stimulation and tumor elimination. These findings suggest that, by modulating the function of TAMs and reshaping an immunosuppressive TME, the SLNP@CpG nanomedicine developed here may become a promising immunotherapeutic option applicable to a variety of tumors.

Anti-inflammatory Glycocalyx-Mimicking Nanoparticles for Colitis Treatment: Construction and In Vivo Evaluation.

Common medications for treating inflammatory bowel disease (IBD) have limited therapeutic efficacy and severe adverse effects. This underscores the urgent need for novel therapeutic approaches that can effectively target inflamed sites in the gastrointestinal tract upon oral administration, exerting potent therapeutic efficacy while minimizing systemic effects. Here, we report the construction and in vivo therapeutic evaluation of a library of anti-inflammatory glycocalyx-mimicking nanoparticles (designated GlyNPs) in a mouse model of IBD. The anti-inflammatory GlyNP library was created by attaching bilirubin (BR) to a library of glycopolymers composed of random combinations of the five most naturally abundant sugars. Direct in vivo screening of 31 BR-attached anti-inflammatory GlyNPs via oral administration into mice with acute colitis led to identification of a candidate GlyNP capable of targeting macrophages in the inflamed colon and effectively alleviating colitis symptoms. These findings suggest that the BR-attached GlyNP library can be used as a platform to identify anti-inflammatory nanomedicines for various inflammatory diseases.

Impeding the Medical Protective Clothing Contamination by a Spray Coating of Trifunctional Polymers.

The risk of fomite-mediated transmission in the clinic is substantially increasing amid the recent COVID-19 pandemic as personal protective equipment (PPE) of hospital workers is easily contaminated by direct contact with infected patients. In this context, it is crucial to devise a means to reduce such transmission. Herein, we report an antimicrobial, antiviral, and antibiofouling trifunctional polymer that can be easily coated onto the surface of medical protective clothing to effectively prevent pathogen contamination on the PPE. The coating layer is formed on the surfaces of PPE by the simple spray coating of an aqueous solution of the trifunctional polymer, poly(dodecyl methacrylate (DMA)-poly(ethylene glycol) methacrylate (PEGMA)-quaternary ammonium (QA)). To establish an optimal ratio of antifouling and antimicrobial functional groups, we performed antifouling, antibacterial, and antiviral tests using four different ratios of the polymers. Antifouling and bactericidal results were assessed using Staphylococcus aureus, a typical pathogenic bacterium that induces an upper respiratory infection. Regardless of the molar ratio, polymer-coated PPE surfaces showed considerable antiadhesion (∼65-75%) and antibacterial (∼75-87%) efficacies soon after being in contact with pathogens and maintained their capability for at least 24 h, which is sufficient for disposable PPEs. Further antiviral tests using coronaviruses showed favorable results with PPE coated at two specific ratios (3.5:6:0.5 and 3.5:5.5:1) of poly(DMA-PEGMA-QA). Moreover, biocompatibility assessments using the two most effective polymer ratios showed no recognizable local or systemic inflammatory responses in mice, suggesting the potential of this polymer for immediate use in the field.

Altered resting-state functional connectivity in women with chronic fatigue syndrome.

The biological underpinnings of the psychological factors characterizing chronic fatigue syndrome (CFS) have not been extensively studied. Our aim was to evaluate alterations of resting-state functional connectivity in CFS patients. Participants comprised 18 women with CFS and 18 age-matched female healthy controls who were recruited from the local community. Structural and functional magnetic resonance images were acquired during a 6-min passive-viewing block scan. Posterior cingulate cortex seeded resting-state functional connectivity was evaluated, and correlation analyses of connectivity strength were performed. Graph theory analysis of 90 nodes of the brain was conducted to compare the global and local efficiency of connectivity networks in CFS patients with that in healthy controls. The posterior cingulate cortex in CFS patients showed increased resting-state functional connectivity with the dorsal and rostral anterior cingulate cortex. Connectivity strength of the posterior cingulate cortex to the dorsal anterior cingulate cortex significantly correlated with the Chalder Fatigue Scale score, while the Beck Depression Inventory (BDI) score was controlled. Connectivity strength to the rostral anterior cingulate cortex significantly correlated with the Chalder Fatigue Scale score. Global efficiency of the posterior cingulate cortex was significantly lower in CFS patients, while local efficiency showed no difference from findings in healthy controls. The findings suggest that CFS patients show inefficient increments in resting-state functional connectivity that are linked to the psychological factors observed in the syndrome.

Compromised Prefrontal Cognitive Control Over Emotional Interference in Adolescents with Internet Gaming Disorder.

Increased reports of impulsivity and aggression in male adolescents with Internet gaming might reflect their dysfunction in emotion regulation, particularly in suppression of negative emotions, which should affect the various stages of Internet gaming disorder. This study tested the hypothesis that adolescents with Internet gaming disorder would be more disturbed by the emotional interference and demonstrate compromised dorsal anterior cingulate cortex (dACC) activation during a Stroop Match-to-Sample task. In addition, functional connectivity analysis was conducted to examine the interplays between neural correlates involved in emotional processing and how they were altered in adolescents with Internet gaming disorder. The Internet gaming disorder group demonstrated weaker dACC activation and stronger insular activations to interfering angry facial stimuli compared with the healthy control group. Negative functional connectivity between stronger insular activation and weaker dorsolateral prefrontal activation correlated with higher cognitive impulsivity in adolescents with Internet gaming disorder. These findings provide evidence of the compromised prefrontal cognitive control over emotional interference in adolescents with Internet gaming disorder.

Resting-state synchrony between anterior cingulate cortex and precuneus relates to body shape concern in anorexia nervosa and bulimia nervosa.

Cortical areas supporting cognitive control and salience demonstrate different neural responses to visual food cues in patients with eating disorders. This top-down cognitive control, which interacts with bottom-up appetitive responses, is tightly integrated not only in task conditions but also in the resting-state. The dorsal anterior cingulate cortex (dACC) is a key node of a large-scale network that is involved in self-referential processing and cognitive control. We investigated resting-state functional connectivity of the dACC and hypothesized that altered connectivity would be demonstrated in cortical midline structures involved in self-referential processing and cognitive control. Seed-based resting-state functional connectivity was analyzed in women with anorexia nervosa (N=18), women with bulimia nervosa (N=20) and age matched healthy controls (N=20). Between group comparisons revealed that the anorexia nervosa group exhibited stronger synchronous activity between the dACC and retrosplenial cortex, whereas the bulimia nervosa group showed stronger synchronous activity between the dACC and medial orbitofrontal cortex. Both groups demonstrated stronger synchronous activity between the dACC and precuneus, which correlated with higher scores of the Body Shape Questionnaire. The dACC-precuneus resting-state synchrony might be associated with the disorder-specific rumination on eating, weight and body shape in patients with eating disorders.

Disruption of orbitofronto-striatal functional connectivity underlies maladaptive persistent behaviors in alcohol-dependent patients.

OBJECTIVE: Alcohol dependence is characterized by persistent alcohol-seeking despite negative consequences. Previous studies suggest that maladaptive persistent behaviors reflect alcohol-induced brain changes that cause alterations in the cortico-striatal-limbic circuit. METHODS: Twenty one alcohol dependent patients and 24 age-matched healthy controls performed a decision-making task during functional MRI. We defined the medial orbitofrontal cortex (mOFC) as a region-of-interest and performed seed-based functional connectivity analysis. RESULTS: Healthy controls were more flexible in adapting an alternative behavioral strategy, which correlated with stronger mOFC-dorsal striatum functional connectivity. In contrast, alcohol dependent patients persisted to the first established behavioral strategy. The mOFC-dorsal striatum functional connectivity was impaired in the alcohol-dependent patients, but increased in correlation with the duration of abstinence. CONCLUSION: Our findings support that the disruption of the mOFC-striatal circuitry contribute to the maldaptive persistent behaviors in alcohol dependent patients.