Cuproptosis, the novel type of oxidation-induced cell death in thoracic cancers: can it enhance the success of immunotherapy?

Copper is an important metal micronutrient, required for the balanced growth and normal physiological functions of human organism. Copper-related toxicity and dysbalanced metabolism were associated with the disruption of intracellular respiration and the development of various diseases, including cancer. Notably, copper-induced cell death was defined as cuproptosis which was also observed in malignant cells, representing an attractive anti-cancer instrument.

Dual effects of radiotherapy on tumor microenvironment and its contribution towards the development of resistance to immunotherapy in gastrointestinal and thoracic cancers.

Successful clinical methods for tumor elimination include a combination of surgical resection, radiotherapy, and chemotherapy. Radiotherapy is one of the crucial components of the cancer treatment regimens which allow to extend patient life expectancy. Current cutting-edge radiotherapy research is focused on the identification of methods that should increase cancer cell sensitivity to radiation and activate anti-cancer immunity mechanisms.

AIFM2 promotes hepatocellular carcinoma metastasis by enhancing mitochondrial biogenesis through activation of SIRT1/PGC-1α signaling.

AIFM2 is a crucial NADH oxidase involved in the regulation of cytosolic NAD. However, the role of AIFM2 in the progression of human cancers remains largely unexplored. Here, we elucidated the clinical implications, biological functions, and molecular mechanisms of AIFM2 in hepatocellular carcinoma (HCC).

Conscription of Immune Cells by Light-Activatable Silencing NK-Derived Exosome (LASNEO) for Synergetic Tumor Eradication.

Exosomes derived from natural killer (NK) cells (NEO) constitute promising antineoplastic nano-biologics because of their versatile functions in immune regulation. However, a significant augment of their immunomodulatory capability is an essential need to achieve clinically meaningful treatment outcomes. Light-activatable silencing NK-derived exosomes (LASNEO) are orchestrated by engineering the NEO with hydrophilic small interfering RNA (siRNA) and hydrophobic photosensitizer Ce6.

CircATIC inhibits esophageal carcinoma progression and promotes radiosensitivity by elevating RHCG through sponging miR-10-3p.

Background: Circular RNAs (circRNAs) are implicated in the progression and radiosensitivity of human cancers, including esophageal carcinoma (ESCA). In this study, we aimed to explore the functions of circRNA 5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase/IMP cyclohydrolase (circATIC) in ESCA progression.

Methods: CircATIC expression, miR-10b-3p and Rh family C glycoprotein (RHCG) were examined via quantitative real-time polymerase chain reaction (qRT-PCR), western blot assay or immunohistochemistry (IHC) assay.

Ionizable lipid-assisted efficient hepatic delivery of gene editing elements for oncotherapy.

CRISPR/Cas9-based gene editing has emerged as a powerful biotechnological tool, that relies on Cas9 protein and single guided RNA (sgRNA) to edit target DNA. However, the lack of safe and efficient delivery carrier is one of the crucial factors restricting its clinical transformation. Here, we report an ionizable lipid nanoparticle (iLP181, pa = 6.

Development of A Decahedral Nanoenzyme Capable of Overcoming Hypoxia to Facilitate the Iodine-125 Radiosensitization of Esophageal Cancer.

Radioisotopes have long been leveraged for internal radiotherapy-mediated cancer treatment. However, such therapeutic approaches are associated with serious side effects, and their efficacy is limited by intratumoral hypoxia. Herein, we prepared a folic acid-decorated palladium decahedral platform capable of enhancing the radiotherapeutic efficacy of iodine-125 (I) seed treatment.

Efficient hepatic delivery and protein expression enabled by optimized mRNA and ionizable lipid nanoparticle.

mRNA is a novel class of therapeutic modality that holds great promise in vaccination, protein replacement therapy, cancer immunotherapy, immune cell engineering However, optimization of mRNA molecules and efficient delivery are quite important but challenging for its broad application. Here we present an ionizable lipid nanoparticle (iLNP) based on iBL0713 lipid for and expression of desired proteins using codon-optimized mRNAs. mRNAs encoding luciferase or erythropoietin (EPO) were prepared by transcription and formulated with proposed iLNP, to form iLP171/mRNA formulations.

A photo-triggerable aptamer nanoswitch for spatiotemporal controllable siRNA delivery.

A photo-triggerable aptamer nanoswitch was proposed for spatiotemporal regulation of siRNA delivery. Recognition between AS1411 and nucleolin was effectively blocked by a photo-labile complementary oligonucleotide, which could be reactivated with photo-irradiation, resulting in efficient tumor-targeted siRNA internalization and gene silencing in vitro and in vivo.

Continuous Vector-free Gene Transfer with a Novel Microfluidic Chip and Nanoneedle Array.

Background: Delivery of foreign cargoes into cells is of great value for bioengineering research and therapeutic applications.

Objective: In this study, we proposed and established a carrier-free gene delivery platform utilizing staggered herringbone channel and silicon nanoneedle array, to achieve high-throughput in vitro gene transfection.

Methods: With this microchip, fluidic micro vortices could be induced by the staggered-herringboneshaped grooves within the channel, which increased the contact frequency of the cells with the channel substrate.

Quantitative Proteomic Analysis of Cell Responses to Electroporation, a Classical Gene Delivery Approach.

Electroporation, as an established nonviral technology for breaching cell membrane, has been accepted for the delivery of nucleic acids. Despite satisfactory delivery efficiencies have been achieved on multiple cell kinds by simply exhausting all possible electrical parameters, electroporation is still inefficient, or even invalid, for various kinds of cells. This is largely due to the lack of comprehensive understanding of cell responses to electrical stimulation at biological aspect.

The study of relationships between pKa value and siRNA delivery efficiency based on tri-block copolymers.

Tri-block copolymers have exhibited great potentials in small interfering RNA (siRNA) therapeutics. To reveal structure-activity relationships, we here synthesized a series of tri-block copolymers with different hydrophobic segments, PEG-PAMA-P(C6A-C7A-DPA-DBA) (EAAS) and PEG-PDAMAEMA-P(C6A-C7A-DPA-DBA) (EDAS), termed from EAASa to EAASh and EDASa to EDASh, with pKa ranging from 5.2 to 7.

Efficient delivery of nucleic acid molecules into skin by combined use of microneedle roller and flexible interdigitated electroporation array.

Delivery of nucleic acid molecules into skin remains a main obstacle for various types of gene therapy or vaccine applications. Here we propose a novel electroporation approach combined use of a microneedle roller and a flexible interdigitated electroporation array (FIEA) for efficient delivery of DNA and siRNA into mouse skin. Using micromachining technology, closely spaced gold electrodes were made on a pliable parylene substrate to form a patch-like electroporation array, which enabled close surface contact between the skin and electrodes.

Parametric optimization of electric field strength for cancer electrochemotherapy on a chip-based model.

Electrochemotherapy (ECT), as one of the very few available treatments for cutaneous and subcutaneous tumors when surgery and radiotherapy are no longer available, requires applying a proper electric field to the tumor to realize electroporation-mediated cytotoxic drug delivery. It is impossible to exhaust all possible electrical parameters on patients to realize the optimal tradeoff between tumor suppression and adverse effects. To address this issue, this study provides a feasible solution by developing a four-leaf micro-electrode chip (F-MEC) in which the electric field was specially designed by linear distribution to cover all possible electric field strengths for ECT.

Elaboration on the Distribution of Hydrophobic Segments in the Chains of Amphiphilic Cationic Polymers for Small Interfering RNA Delivery.

Hydrophobization of cationic polymers, as an efficient strategy, had been widely developed in the structure of cationic polymer micelles to improve the delivery efficiency of nucleic acids. However, the distribution of hydrophobic segments in the polymer chains is rarely considered. Here, we have elaborated three types of hydrophobized polyethylene glycol (PEG)-blocked cationic polymers with different distributions of the hydrophobic segments in the polymer chains PEG-PAM-PDP (E-A-D), PEG-PDP-PAM (E-D-A), and PEG-P(AM/DP) (E-(A/D)), which were synthesized by reversible addition-fragmentation chain transfer polymerization of methoxy PEG, cationic monomer aminoethyl methacrylate, and pH-sensitive hydrophobic monomer 2-diisopropylaminoethyl methacrylate, respectively.

pH-Sensitive Nanomicelles for High-Efficiency siRNA Delivery in Vitro and in Vivo: An Insight into the Design of Polycations with Robust Cytosolic Release.

The extremely low efficient cytosolic release of the internalized siRNA has emerged recently as a central issue for siRNA delivery, while there is a lack of guidelines to facilitate the cytosolic release of internalized siRNA. To address these concerns, we studied the contribution of the pH-sensitive inner core on handling the cytosolic release of siRNA delivered by a series of PG-P(DPAx-co-DMAEMAy)-PCB amphiphilic polycation nanomicelles (GDDC-Ms) with extremely low internalization (<1/4 of lipofactamine 2000 (Lipo2000)). Significantly, just by varying the mole ratio of DPA and DMAEMA to adjust the initial disassembly pH (pH) of the core near to 6.

Pharmacokinetic Behaviors of Intravenously Administered siRNA in Glandular Tissues.

The pharmacokinetics of small interfering RNAs (siRNAs) is a pivotal issue for siRNA-based drug development. In this study, we comprehensively investigated the behavior of siRNAs in vivo in various tissues and demonstrated that intravenously-injected naked siRNA accumulated remarkably in the submandibular gland, bulbourethral gland, and pancreas, with a respective half-life of ~22.7, ~45.

A Flow-Through Cell Electroporation Device for Rapidly and Efficiently Transfecting Massive Amounts of Cells in vitro and ex vivo.

Continuous cell electroporation is an appealing non-viral approach for genetically transfecting a large number of cells. Yet the traditional macro-scale devices suffer from the unsatisfactory transfection efficiency and/or cell viability due to their high voltage, while the emerging microfluidic electroporation devices is still limited by their low cell processing speed. Here we present a flow-through cell electroporation device integrating large-sized flow tube and small-spaced distributed needle electrode array.

Electroporation on microchips: the harmful effects of pH changes and scaling down.

Electroporation has been widely used in delivering foreign biomolecules into cells, but there is still much room for improvement, such as cell viability and integrity. In this manuscript, we investigate the distribution and the toxicity of pH changes during electroporation, which significantly decreases cell viability. A localized pH gradient forms between anode and cathode leading to a localized distribution of cell death near the electrodes, especially cathodes.

A circulating miRNA signature as a diagnostic biomarker for non-invasive early detection of breast cancer.

Novel, non-invasive biomarkers to diagnose breast cancer with high sensitivity and specificity are greatly desired. Circulating microRNAs (miRNAs) show potential for breast cancer detection, but the existing results appear to be mixed. Using microscale serum, we established a novel serum-direct multiplex detection assay based on RT-PCR (SdM-RT-PCR).

A pliable electroporation patch (ep-Patch) for efficient delivery of nucleic acid molecules into animal tissues with irregular surface shapes.

Delivery of nucleic acids into animal tissues by electroporation is an appealing approach for various types of gene therapy, but efficiency of existing methodsis not satisfactory. Here we present the validation of novel electroporation patch (ep-Patch) for efficient delivery of DNA and siRNA into mouse tissues. Using micromachining technology, closely spaced gold electrodes were made on the pliable parylene substrate to form a patch-like electroporation metrics.

Flow-through cell electroporation microchip integrating dielectrophoretic viable cell sorting.

Microfluidics based continuous cell electroporation is an appealing approach for high-throughput cell transfection, but cell viability of existing methods is usually compromised by adverse electrical or hydrodynamic effects. Here we present the validation of a flow-through cell electroporation microchip, in which dielectrophoretic force was employed to sort viable cells. By integrating parallel electroporation electrodes and dielectrophoresis sorting electrodes together in a simple straight microfluidic channel, sufficient electrical pulses were applied for efficient electroporation, and a proper sinusoidal electrical field was subsequently utilized to exclude damaged cells by dielectrophoresis.

High-density distributed electrode network, a multi-functional electroporation method for delivery of molecules of different sizes.

We present a multi-functional electroporation method for delivery of biomolecule utilizing a high-density distributed electrode network (HDEN) under tri-phase electric stimulation. The HDEN device, with which drastic pH change during the electroporation was avoided,was demonstrated to be highly effective for transfection of not only DNA plasmids and small interfering RNAs (siRNA), but also a small molecular anti-cancer drug, into cells in adjustable volumes of cell suspension. The method constitutes a very flexible electroporation approach in a wide range of in vitro or ex vivo scenarios in various tubes, standard multi-well plates as well as flow chambers.

Method for electric parametric characterization and optimization of electroporation on a chip.

We have developed a rapid method to optimize the electric parameters of cell electroporation. In our design, a pair of ring-dot formatted electrodes was used to generate a radial distribution of electric field from the center to the periphery. Varied electric field intensity was acquired in different annulus when an electric pulse was applied.

Circulating microRNA-122 as a potential biomarker for liver injury.

Liver-specific microRNA-122 (miR-122) is involved in the replication of hepatitis C virus (HCV) and its potential as a target for antiviral intervention was recently assessed. However, the use of circulating miR-122 in the evaluation of liver function has never been reported. In the present study, changes of serum miRNA levels were first evaluated in acute human hepatotoxicity due to paraquat exposure.