Reconciling the Cooperative-Competitive Patterns among Tumor and Immune Cells for Triple-Negative Breast Cancer Treatment Using Multimodule Nanocomplexes.

Targeting the competitive-cooperative relationships among tumor cells and various immune cells can efficiently reverse the immune-dysfunction microenvironment to boost the immunotherapies for the triple-negative breast cancer treatment. Hence, a bacterial outer membrane vesicle-based nanocomplex is designed for specifically targeting malignant cells and immune cells to reconcile the relationships based on metabolic-immune crosstalk. By uniquely utilizing the property of charge-reversal polymers to realize function separation, the nanocomplexes could synergistically regulate tumor cells and immune cells.

A New HEK293 Cell with CR2 Region of E1A Gene Deletion Prevents the Emergence of Replication-Competent Adenovirus.

Purpose: To eliminate the contaminants of Replication-Competent Adenovirus (RCA) during high titer recombinant oncolytic adenovirus production.

Methods: At first, we detected E1A copy numbers of different sources of 293 cells using Q-PCR, and we screened a subclone JH293-C21 of the JH293 cell line (purchased from ATCC) with lower early region 1A (E1A) copy numbers and higher adenovirus production ability. Then, we deleted the conserved region (CR)2 of the E1A gene in this subclone using the CRISPR-Cas9 system and obtained a stable cell clone JH293-C21-C14 with lower E1A expression, but the RCA formation had no significant reduction.

Nanomaterials with dual immunomodulatory functions for synergistic therapy of breast cancer brain metastases.

A long-standing paucity of effective therapies results in the poor outcomes of triple-negative breast cancer brain metastases. Immunotherapy has made progress in the treatment of tumors, but limited by the non-immunogenicity of tumors and strong immunosuppressive environment, patients with TNBC brain metastases have not yet benefited from immunotherapy. Dual immunoregulatory strategies with enhanced immune activation and reversal of the immunosuppressive microenvironment provide new therapeutic options for patients.

ROS-removing nano-medicine for navigating inflammatory microenvironment to enhance anti-epileptic therapy.

As a neurological disorder in the brain, epilepsy is not only associated with abnormal synchronized discharging of neurons, but also inseparable from non-neuronal elements in the altered microenvironment. Anti-epileptic drugs (AEDs) merely focusing on neuronal circuits frequently turn out deficient, which is necessitating comprehensive strategies of medications to cover over-exciting neurons, activated glial cells, oxidative stress and chronic inflammation synchronously. Therefore, we would report the design of a polymeric micelle drug delivery system that was functioned with brain targeting and cerebral microenvironment modulation.

A neutrophil-biomimic platform for eradicating metastatic breast cancer stem-like cells by redox microenvironment modulation and hypoxia-triggered differentiation therapy.

Metastasis accounts for 90% of breast cancer deaths, where the lethality could be attributed to the poor drug accumulation at the metastatic loci. The tolerance to chemotherapy induced by breast cancer stem cells (BCSCs) and their particular redox microenvironment further aggravate the therapeutic dilemma. To be specific, therapy-resistant BCSCs can differentiate into heterogeneous tumor cells constantly, and simultaneously dynamic maintenance of redox homeostasis promote tumor cells to retro-differentiate into stem-like state in response to cytotoxic chemotherapy.

Compound Nanoemulsion Combined with Differentiation/Cytotoxicity Drugs for Modulating Breast Cancer Stemness.

Breast cancer stem cells (BCSCs) are the culprit of triple-negative breast cancer invasiveness and are heterogeneous. It is recognized that the combination of chemotherapy and differentiation therapy for killing BCSCs and non-BCSCs simultaneously is a reliable strategy. In this study, an oil-in-water nanoemulsion was prepared by high-pressure homogenization with coencapsulation of all-trans retinoic acid (ATRA) and doxorubicin (DOX).

The Effect of Education Model in Physical Education on Student Learning Behavior.

This research explores the effect of the sports education model implemented in physical education on college students' learning motivation and outcomes. The sports education model was compared with traditional physical education teaching as a control group. Participants were 60 college students in two classes.

Microenvironment-tailored micelles restrain carcinoma-astrocyte crosstalk for brain metastasis.

Breast-to-brain metastatic cells can interact with the surrounding cells, including astrocytes and microglia, to generate a pro-tumorigenic niche. Breast-to-brain metastasis can be treated using a dual strategy of eliminating metastatic tumor cells and normalizing their localized microenvironment. The effective accumulation of drugs at the action site of metastasis is crucial to realizing the above strategy, especially when dealing with the blood-brain barrier (BBB)-penetrating and tumor-targeting tactics.

An effective therapeutic regime for treatment of glioma using oncolytic vaccinia virus expressing IL-21 in combination with immune checkpoint inhibition.

Glioblastoma (GBM) is the most common primary malignant tumor in the brain, accounting for 51.4% of all primary brain tumors. GBM has a highly immunosuppressive tumor microenvironment (TME) and, as such, responses to immunotherapeutic strategies are poor.

Smart hypoxia-responsive transformable and charge-reversible nanoparticles for the deep penetration and tumor microenvironment modulation of pancreatic cancer.

The compact extracellular matrix (ECM) of pancreatic ductal adenocarcinoma (PDAC) is the major physical barrier that hinders the delivery of anti-tumor drugs, leading to strong inherent chemotherapy resistance as well as establishing an immunosuppressive tumor microenvironment (TME). However, forcibly destroying the stroma barrier would break the balance of delicate signal transduction and dependence between tumor cells and matrix components. Uncontrollable growth and metastasis would occur, making PDAC more difficult to control.

Penetrating Micelle for Reversing Immunosuppression and Drug Resistance in Pancreatic Cancer Treatment.

Pancreatic ductal adenocarcinoma (PDAC) is on of the most lethal malignant tumors with relatively poor prognosis, characterized with insufficient drug penetration, low immune response and obvious drug resistances. The therapeutic inefficiency is multifactorially related to its specific tumor microenvironment (TME), which is representatively featured as rich stroma and immunosuppression. In this work, a versatile drug delivery system is developed that can coencapsulate two prodrugs modified from gemcitabine (GEM) and a signal transducer and activator of transcription 3 (STAT3) inhibitor (HJC0152), and the gradient pH variation is further sensed in the TME of PDAC to achieve a higher penetration by reversing its surficial charges.

Physicochemical Characterization and Pharmacological Evaluation of Novel Propofol Micelles with Low-Lipid and Low-Free Propofol.

We developed safe and stable mixed polymeric micelles with low lipids and free propofol for intravenous administration, to overcome the biological barrier of the reticuloendothelial system (RES), reduce pain upon injection, and complications of marketed propofol formulation. The propofol-mixed micelles were composed of distearoyl-phosphatidylethanolamine-methoxy-poly (ethylene glycol 2000) (DSPE mPEG2k) and Solutol HS 15 and were optimized using Box Behnken design (BBD). The optimized formulation was evaluated for globule size, zeta potential, loading content, encapsulation efficiency, pain on injection, histological evaluation, hemolysis test, in vivo anesthetic action, and pharmacokinetics, in comparison to the commercialized emulsion Diprivan.

Exosomes derived from immunogenically dying tumor cells as a versatile tool for vaccination against pancreatic cancer.

Despite tremendous progress achieved in immunotherapy, many critical challenges in treating pancreatic ductal adenocarcinoma (PDAC) persist. Considering the poor vascularization of PDAC, after intramuscular administration exosomes can targeted deliver "cargos" to pancreatic tumors and bypass obstructions of the intrinsic overexpressed stroma through lymphatics. Herein, we propose a strategy to derive exosomes from immunogenically dying tumor cells and exploit their properties for several purposes, including antigen presentation, adjuvant supply, and "cargo" delivery of vaccines against pancreatic cancer via intramuscular injection.

A Micro-Environment Regulator for Filling the Clinical Treatment Gap after a Glioblastoma Operation.

The rapid postoperative recurrence and short survival time of glioblastoma (GBM) patients necessitate immediate and effective postoperative treatment. Herein, an immediate and mild postoperative local treatment strategy is developed that regulates the postoperative microenvironment and delays GBM recurrence. Briefly, an injectable hydrogel system (imGEL) loaded with Zn(II) -AMD3100 (AMD-Zn) and CpG oligonucleotide nanoparticles (CpG NPs) is injected into the operation cavity, with long-term function to block the recruitment of microglia/ macrophages and activate cytotoxic T cells.

Macrophage-Disguised Manganese Dioxide Nanoparticles for Neuroprotection by Reducing Oxidative Stress and Modulating Inflammatory Microenvironment in Acute Ischemic Stroke.

Reperfusion injury is still a major challenge that impedes neuronal survival in ischemic stroke. However, the current clinical treatments are remained on single pathological process, which are due to lack of comprehensive neuroprotective effects. Herein, a macrophage-disguised honeycomb manganese dioxide (MnO ) nanosphere loaded with fingolimod (FTY) is developed to salvage the ischemic penumbra.

A Versatile Theranostic Platform for Colorectal Cancer Peritoneal Metastases: Real-Time Tumor-Tracking and Photothermal-Enhanced Chemotherapy.

A versatile tumor-targeting stimuli-responsive theranostic platform for peritoneal metastases of colorectal cancer is proposed in this work for tumor tracking and photothermal-enhanced chemotherapy. A quenched photosensitizer ("off" state) is developed and escorted into a tumor-targeting oxaliplatin-embedded micelle. Once reaching the tumor cell, the micelle is clasped to release free oxaliplatin, as well as the "off" photosensitizer, which is further activated ("turned-on") in the tumor reducing microenvironment to provide optical imaging and photothermal effect.

Sequentially Triggered Bacterial Outer Membrane Vesicles for Macrophage Metabolism Modulation and Tumor Metastasis Suppression.

Metabolic interactions between different cell types in the tumor microenvironment (TME) often result in reprogramming of the metabolism to be totally different from their normal physiological processes in order to support tumor growth. Many studies have attempted to inhibit tumor growth and activate tumor immunity by regulating the metabolism of tumors and other cells in TME. However, metabolic inhibitors often suffer from the heterogeneity of tumors, since the favorable metabolic regulation of malignant cells and other cells in TME is often inconsistent with each other.

Biomimetic Dendrimer-Peptide Conjugates for Early Multi-Target Therapy of Alzheimer's Disease by Inflammatory Microenvironment Modulation.

Current therapeutic strategies for Alzheimer's disease (AD) treatments mainly focus on β-amyloid (Aβ) targeting. However, such therapeutic strategies have limited clinical outcomes due to the chronic and irreversible impairment of the nervous system in the late stage of AD. Recently, inflammatory responses, manifested in oxidative stress and glial cell activation, have been reported as hallmarks in the early stages of AD.

A novel vaccinia virus enhances anti-tumor efficacy and promotes a long-term anti-tumor response in a murine model of colorectal cancer.

Colorectal cancer (CRC) is one of the leading causes of mortality and morbidity in the world, and there remains an urgent need to develop long-lasting therapies to treat CRC and prevent recurrence in patients. Oncolytic virus therapy (OVT) has demonstrated remarkable efficacy in a number of different cancer models. Here, we report a novel vaccinia virus (VV)-based OVT for treatment of CRC.

Click-Nucleic-Acid-Containing Codelivery System Inducing Collapse of Cellular Homeostasis for Tumor Therapy through Bidirectional Regulation of Autophagy and Glycolysis.

As a rapid proliferating tissue, tumor cells have to optimize nutrient utilization to withstand harsh conditions. Several approaches have been explored to inhibit the growth and metastasis of tumor by disrupting the reprogrammed tumor metabolism. However, nutrient limitations within solid tumors may induce the metabolic flexibility of malignant cells to sustain growth and survival using one nutrient to fill metabolite pools normally supplied by the other.

Pancreatic cancer-targeting exosomes for enhancing immunotherapy and reprogramming tumor microenvironment.

Immunotherapy has gained increasing focus in treating pancreatic ductal adenocarcinoma (PDAC), since conventional therapies like chemotherapy could not provide satisfactory improvement in overall survival outcome of PDAC patients. However, it is still not the game changing solution due to the unique tumor microenvironment and low cancer immunogenicity of PDAC. Thus, inducing more intratumoral effector immune cells as well as reversing immunosuppression is the core of PDAC treatment.

Penetrable Nanoplatform for "Cold" Tumor Immune Microenvironment Reeducation.

Lack of tumor-infiltration lymphocytes (TILs) and resistances by overexpressed immunosuppressive cells (principally, myeloid-derived suppressor cells (MDSCs)) in tumor milieu are two major challenges hindering the effectiveness of immunotherapy for "immune-cold" tumors. In addition, the natural physical barrier existing in solid cancer also limits deeper delivery of drugs. Here, a tumor-targeting and light-responsive-penetrable nanoplatform (Apt/PDGss@pMOF) is developed to elicit intratumoral infiltration of cytotoxic T cells (CTLs) and reeducate immunosuppressive microenvironment simultaneously.

Treatment and Prevention of Lung Cancer Using a Virus-Infected Reprogrammed Somatic Cell-Derived Tumor Cell Vaccination (VIReST) Regime.

Lung cancer is one of the most commonly diagnosed cancer and despite therapeutic advances, mortality remains high. The long period of clinical latency associated with lung cancer provides an ideal window of opportunity to administer vaccines to at-risk individuals that can prevent tumor progression and initiate long-term anti-tumor immune surveillance. Here we describe a personalized vaccination regime that could be applied for both therapeutic and prophylactic prevention of lung cancer, based on the derivation of lung cancer cells from induced pluripotent stem cells.

Carry-On Nitric-Oxide Luggage for Enhanced Chemotherapeutic Efficacy.

In this work, we proposed a carry-on nitric-oxide (NO) luggage strategy for enhanced chemotherapeutic efficacy. A stimuli-responsive NO-releasing polypeptide was prepared as the building block to assemble into a micelle as a chemodrug-carrier. The micelle was anchored with cRGD peptide with the aim of targeting to tumors' neoangiogenesis.