Engineering therapeutical extracellular vesicles for clinical translation.

Cell-based therapies are revolutionizing medicine by replacing or modifying dysfunctional cells with healthy cells or engineered derivatives, offering disease reversal and cure. One promising approach is using cell-derived extracellular vesicles (EVs), which offer therapeutic benefits similar to cell transplants without the biosafety risks. Although EV applications face challenges like limited production, inadequate therapeutic loading, and poor targeting efficiency, recent advances in bioengineering have enhanced their effectiveness.

Regulation of cerebral blood flow boosts precise brain targeting of vinpocetine-derived ionizable-lipidoid nanoparticles.

Despite advances in active drug targeting for blood-brain barrier penetration, two key challenges persist: first, attachment of a targeting ligand to the drug or drug carrier does not enhance its brain biodistribution; and second, many brain diseases are intricately linked to microcirculation disorders that significantly impede drug accumulation within brain lesions even after they cross the barrier. Inspired by the neuroprotective properties of vinpocetine, which regulates cerebral blood flow, we propose a molecular library design centered on this class of cyclic tertiary amine compounds and develop a self-enhanced brain-targeted nucleic acid delivery system. Our findings reveal that: (i) vinpocetine-derived ionizable-lipidoid nanoparticles efficiently breach the blood-brain barrier; (ii) they have high gene-loading capacity, facilitating endosomal escape and intracellular transport; (iii) their administration is safe with minimal immunogenicity even with prolonged use; and (iv) they have potent pharmacologic brain-protective activity and may synergize with treatments for brain disorders as demonstrated in male APP/PS1 mice.

Synthetic cationic helical polypeptides for the stimulation of antitumour innate immune pathways in antigen-presenting cells.

Intracellular DNA sensors regulate innate immunity and can provide a bridge to adaptive immunogenicity. However, the activation of the sensors in antigen-presenting cells (APCs) by natural agonists such as double-stranded DNAs or cyclic nucleotides is impeded by poor intracellular delivery, serum stability, enzymatic degradation and rapid systemic clearance. Here we show that the hydrophobicity, electrostatic charge and secondary conformation of helical polypeptides can be optimized to stimulate innate immune pathways via endoplasmic reticulum stress in APCs.

A Cancer Nanovaccine Based on an FeAl-Layered Double Hydroxide Framework for Reactive Oxygen Species-Augmented Metalloimmunotherapy.

The complexity and heterogeneity of individual tumors have hindered the efficacy of existing therapeutic cancer vaccines, sparking intensive interest in the development of more effective vaccines. Herein, we introduce a cancer nanovaccine for reactive oxygen species-augmented metalloimmunotherapy in which FeAl-layered double hydroxide (LDH) is used as a delivery vehicle with dihydroartemisinin (DHA) as cargo. The LDH framework is acid-labile and can be degraded in the tumor microenvironment, releasing iron ions, aluminum ions, and DHA.

Bio-integrated scaffold facilitates large bone regeneration dominated by endochondral ossification.

Repair of large bone defects caused by severe trauma, non-union fractures, or tumor resection remains challenging because of limited regenerative ability. Typically, these defects heal through mixed routines, including intramembranous ossification (IMO) and endochondral ossification (ECO), with ECO considered more efficient. Current strategies to promote large bone healing via ECO are unstable and require high-dose growth factors or complex cell therapy that cause side effects and raise expense while providing only limited benefit.

Radiation Synergizes with IL2/IL15 Stimulation to Enhance Innate Immune Activation and Antitumor Immunity.

Ionizing radiation is known to possess immune modulatory properties. However, how radiotherapy (RT) may complement with different types of immunotherapies to boost antitumor responses is unclear. In mice implanted with EO771 syngeneic tumors, NL-201 a stable, highly potent CD25-independent agonist to IL2 and IL15 receptors with enhanced affinity for IL2Rβγ was given with or without RT.

Adaptive design of mRNA-loaded extracellular vesicles for targeted immunotherapy of cancer.

The recent success of mRNA therapeutics against pathogenic infections has increased interest in their use for other human diseases including cancer. However, the precise delivery of the genetic cargo to cells and tissues of interest remains challenging. Here, we show an adaptive strategy that enables the docking of different targeting ligands onto the surface of mRNA-loaded small extracellular vesicles (sEVs).

Age-associated disparity in phagocytic clearance affects the efficacy of cancer nanotherapeutics.

Nanomedicines have been approved to treat multiple human diseases. However, clinical adoption of nanoformulated agents is often hindered by concerns about hepatic uptake and clearance, a process that is not fully understood. Here we show that the antitumour efficacy of cancer nanomedicine exhibits an age-associated disparity.

Targeting phagocytosis to enhance antitumor immunity.

Many patients with metastatic or treatment-resistant cancer have experienced improved outcomes after immunotherapy that targets adaptive immune checkpoints. However, innate immune checkpoints, which can hinder the detection and clearance of malignant cells, are also crucial in tumor-mediated immune escape and may also serve as targets in cancer immunotherapy. In this review, we discuss the current understanding of immune evasion by cancer cells via disruption of phagocytic clearance, and the potential effects of blocking phagocytosis checkpoints on the activation of antitumor immune responses.

Intradermally delivered mRNA-encapsulating extracellular vesicles for collagen-replacement therapy.

The success of messenger RNA therapeutics largely depends on the availability of delivery systems that enable the safe, effective and stable translation of genetic material into functional proteins. Here we show that extracellular vesicles (EVs) produced via cellular nanoporation from human dermal fibroblasts, and encapsulating mRNA encoding for extracellular-matrix α1 type-I collagen (COL1A1) induced the formation of collagen-protein grafts and reduced wrinkle formation in the collagen-depleted dermal tissue of mice with photoaged skin. We also show that the intradermal delivery of the mRNA-loaded EVs via a microneedle array led to the prolonged and more uniform synthesis and replacement of collagen in the dermis of the animals.

Immunological conversion of solid tumours using a bispecific nanobioconjugate for cancer immunotherapy.

Solid tumours display a limited response to immunotherapies. By contrast, haematological malignancies exhibit significantly higher response rates to immunotherapies as compared with solid tumours. Among several microenvironmental and biological disparities, the differential expression of unique immune regulatory molecules contributes significantly to the interaction of blood cancer cells with immune cells.

Correction: Wang et al. Cell-Penetrating Peptide and Transferrin Co-Modified Liposomes for Targeted Therapy of Glioma. 2019, , 3540.

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Hybrid Nanofibrous Composites with Anisotropic Mechanics and Architecture for Tendon/Ligament Repair and Regeneration.

Rupture of tendons and ligaments (T/L) is a major clinical challenge due to T/L possess anisotropic mechanical properties and hierarchical structures. Here, to imitate these characteristics, an approach is presented by fabricating hybrid nanofibrous composites. First, hybrid fiber-reinforced yarns are fabricated via successively electrospinning poly(L-lactide-co-ε-caprolactone) (PLCL) and gelatin (Ge) nanofibers onto polyethylene terephthalate (PET) fibers to improve biodurability and biocompatibility.

Dual-Loaded Liposomes Tagged with Hyaluronic Acid Have Synergistic Effects in Triple-Negative Breast Cancer.

Triple-negative breast cancer (TNBC) is the most lethal subtypes of breast cancer. Although chemotherapy is considered the most effective strategy for TNBC, most chemotherapeutics in current use are cytotoxic, meaning they target antiproliferative activity but do not inhibit tumor cell metastasis. Here, a TNBC-specific targeted liposomal formulation of epalrestat (EPS) and doxorubicin (DOX) with synergistic effects on both tumor cell proliferation and metastasis is described.

Transferrin-conjugated liposomes loaded with carnosic acid inhibit liver cancer growth by inducing mitochondria-mediated apoptosis.

Our previous studies have proven that carnosic acid (CA) induces apoptosis of liver cancer cells. However, the poor chemical properties of CA limit its in vivo anti-cancer effects. In this study, CA was loaded into liposomes (LP-CA), and LP-CA was further conjugated with transferrin (Tf-LP-CA) to overcome the shortcomings of poor solubility and absorption at the lesion site.

Emerging Biological Functions of IL-17A: A New Target in Chronic Obstructive Pulmonary Disease?

Chronic obstructive pulmonary disease (COPD) is a chronic inflammatory disease that causes high rates of disability and mortality worldwide because of severe progressive and irreversible symptoms. During the period of COPD initiation and progression, the immune system triggers the activation of various immune cells, including Regulatory T cells (Tregs), dendritic cells (DCs) and Th17 cells, and also the release of many different cytokines and chemokines, such as IL-17A and TGF-β. In recent years, studies have focused on the role of IL-17A in chronic inflammation process, which was found to play a highly critical role in facilitating COPD.

Self-Assembled pH-Sensitive Polymeric Nanoparticles for the Inflammation-Targeted Delivery of Cu/Zn-Superoxide Dismutase.

The use of superoxide dismutase (SOD) is currently limited by its short half-life, rapid plasma clearance rate, and instability. We synthesized a small library of biofriendly amphiphilic polymers that comprise methoxy poly(ethylene glycol)-poly(cyclohexane-1,4-diyl acetone dimethyleneketal) (mPEG-PCADK) and mPEG-poly((cyclohexane, 1,5-pentanediol)-1,4-diyl acetone dimethylene ketal) (PK3) for the targeted delivery of SOD. The novel polymers could self-assemble into micellar nanoparticles with favorable hydrolysis kinetics, biocompatibility, long circulation time, and inflammation-targeting effects.

Extracellular Vesicles: An Emerging Nanoplatform for Cancer Therapy.

Extracellular vesicles (EVs) are cell-derived membrane particles that represent an endogenous mechanism for cell-to-cell communication. Since discovering that EVs have multiple advantages over currently available delivery platforms, such as their ability to overcome natural barriers, intrinsic cell targeting properties, and circulation stability, the potential use of EVs as therapeutic nanoplatforms for cancer studies has attracted considerable interest. To fully elucidate EVs' therapeutic function for treating cancer, all current knowledge about cellular uptake and trafficking of EVs will be initially reviewed.

Extracellular Vesicles in the Treatment of Parkinson's Disease: A Review.

Background: Parkinson's disease (PD) is one of the most common neurological disorders that can severely affect the ability to perform daily activities. The clinical presentation of PD includes motor and nonmotor symptoms. The motor symptoms generally involve movement conditions like tremors, rigidity, slowness, and impaired balance.

Immunocyte Membrane-Coated Nanoparticles for Cancer Immunotherapy.

Despite the advances in surface bioconjugation of synthetic nanoparticles for targeted drug delivery, simple biological functionalization is still insufficient to replicate complex intercellular interactions naturally. Therefore, these foreign nanoparticles are inevitably exposed to the immune system, which results in phagocytosis by the reticuloendothelial system and thus, loss of their biological significance. Immunocyte membranes play a key role in intercellular interactions, and can protect foreign nanomaterials as a natural barrier.

Application of BERT to Enable Gene Classification Based on Clinical Evidence.

The identification of profiled cancer-related genes plays an essential role in cancer diagnosis and treatment. Based on literature research, the classification of genetic mutations continues to be done manually nowadays. Manual classification of genetic mutations is pathologist-dependent, subjective, and time-consuming.

Microfluidic self-assembly of high cabazitaxel loading albumin nanoparticles.

Cabazitaxel (CTX) is a promising anticancer drug. In this study, CTX-loaded human serum albumin (HSA) nanoparticles (MF-NPs-CTX) were prepared by a microfluidic (MF) method and were evaluated for tumor inhibition in PC-3 and HeLa cells in vitro and in vivo. The in vitro experiments showed that MF-NPs-CTX had higher drug loading content (DLC) as compared with NPs prepared by the bottom-up (BU) method (BU-NPs-CTX).

Nanoparticle-Based Drug Delivery System: A Patient-Friendly Chemotherapy for Oncology.

Chemotherapy is widely used to treat cancer. The toxic effect of conventional chemotherapeutic drugs on healthy cells leads to serious toxic and side effects of conventional chemotherapy. The application of nanotechnology in tumor chemotherapy can increase the specificity of anticancer agents, increase the killing effect of tumors, and reduce toxic and side effects.

Cell-Penetrating Peptides in Diagnosis and Treatment of Human Diseases: From Preclinical Research to Clinical Application.

Cell-penetrating peptides (CPPs) are short peptides (fewer than 30 amino acids) that have been predominantly used in basic and preclinical research during the last 30 years. Since they are not only capable of translocating themselves into cells but also facilitate drug or CPP/cargo complexes to translocate across the plasma membrane, they have potential applications in the disease diagnosis and therapy, including cancer, inflammation, central nervous system disorders, otologic and ocular disorders, and diabetes. However, no CPPs or CPP/cargo complexes have been approved by the US Food and Drug Administration (FDA).