Camrelizumab plus rivoceranib versus sorafenib as first-line therapy for unresectable hepatocellular carcinoma (CARES-310): a randomised, open-label, international phase 3 study.

BACKGROUND: Immunotherapy with immune checkpoint inhibitors combined with an anti-angiogenic tyrosine-kinase inhibitor (TKI) has been shown to improve overall survival versus anti-angiogenic therapy alone in advanced solid tumours, but not in hepatocellular carcinoma. Therefore, a clinical study was conducted to compare the efficacy and safety of the anti-PD-1 antibody camrelizumab plus the VEGFR2-targeted TKI rivoceranib (also known as apatinib) versus sorafenib as first-line treatment for unresectable hepatocellular carcinoma. METHODS: This randomised, open-label, international phase 3 trial (CARES-310) was done at 95 study sites across 13 countries and regions worldwide. Patients with unresectable or metastatic hepatocellular carcinoma who had not previously received any systemic treatment were randomly assigned (1:1) to receive either camrelizumab 200 mg intravenously every 2 weeks plus rivoceranib 250 mg orally once daily or sorafenib 400 mg orally twice daily. Randomisation was done via a centralised interactive response system. The primary endpoints were progression-free survival, as assessed by the blinded independent review committee per Response Evaluation Criteria in Solid Tumours version 1.1, and overall survival in the intention-to-treat population. Safety was assessed in all patients who received at least one dose of the study drugs. We report the findings from the prespecified primary analysis for progression-free survival and interim analysis for overall survival. This study is registered with ClinicalTrials.gov (NCT03764293). FINDINGS: Between June 28, 2019, and March 24, 2021, 543 patients were randomly assigned to the camrelizumab-rivoceranib (n=272) or sorafenib (n=271) group. At the primary analysis for progression-free survival (May 10, 2021), median follow-up was 7·8 months (IQR 4·1-10·6). Median progression-free survival was significantly improved with camrelizumab-rivoceranib versus sorafenib (5·6 months [95% CI 5·5-6·3] vs 3·7 months [2·8-3·7]; hazard ratio [HR] 0·52 [95% CI 0·41-0·65]; one-sided p<0·0001). At the interim analysis for overall survival (Feb 8, 2022), median follow-up was 14·5 months (IQR 9·1-18·7). Median overall survival was significantly extended with camrelizumab-rivoceranib versus sorafenib (22·1 months [95% CI 19·1-27·2] vs 15·2 months [13·0-18·5]; HR 0·62 [95% CI 0·49-0·80]; one-sided p<0·0001). The most common grade 3 or 4 treatment-related adverse events were hypertension (102 [38%] of 272 patients in the camrelizumab-rivoceranib group vs 40 [15%] of 269 patients in the sorafenib group), palmar-plantar erythrodysaesthesia syndrome (33 [12%] vs 41 [15%]), increased aspartate aminotransferase (45 [17%] vs 14 [5%]), and increased alanine aminotransferase (35 [13%] vs eight [3%]). Treatment-related serious adverse events were reported in 66 (24%) patients in the camrelizumab-rivoceranib group and 16 (6%) in the sorafenib group. Treatment-related death occurred in two patients: one patient in the camrelizumab-rivoceranib group (ie, multiple organ dysfunction syndrome) and one patient in the sorafenib group (ie, respiratory failure and circulatory collapse). INTERPRETATION: Camrelizumab plus rivoceranib showed a statistically significant and clinically meaningful benefit in progression-free survival and overall survival compared with sorafenib for patients with unresectable hepatocellular carcinoma, presenting as a new and effective first-line treatment option for this population. FUNDING: Jiangsu Hengrui Pharmaceuticals and Elevar Therapeutics.

Boosting Electrochemiluminescence Performance of a Dual-Active Site Iron Single-Atom Catalyst-Based Luminol-Dissolved Oxygen System via Plasmon-Induced Hot Holes.

Due to the commonly low content of biomarkers in diseases, increasing the sensitivity of electrochemiluminescence (ECL) systems is of great significance for in vitro ECL diagnosis and biodetection. Although dissolved O2 (DO) has recently been considered superior to H2O2 as a coreactant in the most widely used luminol ECL systems owing to its improved stability and less biotoxicity, it still has unsatisfactory ECL performance because of its ultralow reactivity. In this study, an effective plasmonic luminol-DO ECL system has been developed by complexing luminol-capped Ag nanoparticles (AgNPs) with plasma-treated Fe single-atom catalysts (Fe-SACs) embedded in graphitic carbon nitride (g-CN) (pFe-g-CN). Under optimal conditions, the performance of the resulting ECL system could be markedly increased up to 1300-fold compared to the traditional luminol-DO system. Further investigations revealed that duple binding sites of pFe-g-CN and plasmonically induced hot holes that disseminated from AgNPs to g-CN surfaces lead to facilitate significantly the luminous reaction process of the system. The proposed luminol-DO ECL system was further employed for the stable and ultrasensitive detection of prostate-specific antigen in a wide linear range of 1.0 fg/mL to 1 µg/mL, with a pretty low limit of detection of 0.183 fg/mL.

"Light-On" Fluorescent Nanoprobes for Monitoring Dynamic Distribution of Cellular Nucleolin During Pyroptosis.

Nucleolin (NCL) is a multifunctional nuclear protein that plays significant roles in regulating physiological activities of the cells. However, it remains a challenge to monitor the dynamic distribution and expression of nucleolin within living cells during cell stress processes directly. Here, we designed "turn-on" fluorescent nanoprobes composed of specific AS1411 aptamer and nucleus-targeting peptide on gold nanoparticles (AuNPs) to effectively capture and track the NCL distribution and expression during pyroptosis triggered by electrical stimulation (ES). The distribution of nucleolin in the cell membrane and nucleus can be easily observed by simply changing the particle size of the nanoprobes. The present strategy exhibits obvious advantages such as simple operation, low cost, time saving, and suitability for living cell imaging. The ES can induce cancer cell pyroptosis controllably and selectively, with less harm to the viability of normal cells. The palpable cell nuclear stress responses of cancerous cells, including nucleus wrinkling and nucleolus fusion after ES at 1.0 V were obviously observed. Compared with normal cells (MCF-10A), NCL is overexpressed within cancerous cells (MCF-7 cells) using the as-designed nanoprobes, and the ES can effectively inhibit NCL expression within cancerous cells. The developed NCL sensing platform and ES-based methods hold great potential for cellular studies of cancer-related diseases.

Long-term survivals of immune checkpoint inhibitors as neoadjuvant and adjuvant therapy in dMMR/MSI-H colorectal and gastric cancers.

BACKGROUND: The long-term survival benefit of immune checkpoint inhibitors (ICIs) in neoadjuvant and adjuvant settings is unclear for colorectal cancers (CRC) and gastric cancers (GC) with deficiency of mismatch repair (dMMR) or microsatellite instability-high (MSI-H). METHODS: This retrospective study enrolled patients with dMMR/MSI-H CRC and GC who received at least one dose of neoadjuvant ICIs (neoadjuvant cohort, NAC) or adjuvant ICIs (adjuvant cohort, AC) at 17 centers in China. Patients with stage IV disease were also eligible if all tumor lesions were radically resectable. RESULTS: In NAC (n = 124), objective response rates were 75.7% and 55.4%, respectively, in CRC and GC, and pathological complete response rates were 73.4% and 47.7%, respectively. The 3-year disease-free survival (DFS) and overall survival (OS) rates were 96% (95%CI 90-100%) and 100% for CRC (median follow-up [mFU] 29.4 months), respectively, and were 84% (72-96%) and 93% (85-100%) for GC (mFU 33.0 months), respectively. In AC (n = 48), the 3-year DFS and OS rates were 94% (84-100%) and 100% for CRC (mFU 35.5 months), respectively, and were 92% (82-100%) and 96% (88-100%) for GC (mFU 40.4 months), respectively. Among the seven patients with distant relapse, four received dual blockade of PD1 and CTLA4 combined with or without chemo- and targeted drugs, with three partial response and one progressive disease. CONCLUSION: With a relatively long follow-up, this study demonstrated that neoadjuvant and adjuvant ICIs might be both associated with promising DFS and OS in dMMR/MSI-H CRC and GC, which should be confirmed in further randomized clinical trials.

Glass Nanopipette-Based Plasmonic SERS Platform for Single-Cell MicroRNA-21 Sensing during Apoptosis.

As one of the most widely distributed microRNAs, microRNA-21 (miRNA-21) significantly regulates target genes' expression levels and participates in many cellular and intercellular activities, and its abnormal expression is always related to some diseases, especially cancer. Hence, detecting miRNA-21, as a biomarker, at the single-cell level helps us to reveal cell heterogeneity and expression level variation during the state change of cells. In this study, we constructed a gold nanoparticles nanomembrane (AuNPs-NM)-modified plasmonic glass nanopipette (P-nanopipette) surface-enhanced Raman scattering (SERS) sensing platform to sensitively detect content variation of the intracellular miRNA-21 during the electrostimulus (ES)-induced apoptosis process. The cytoplasm-located miRNA-21 was first extracted by using the extraction DNA (HP1)-modified P-nanopipette through a hybridization chain reaction (HCR). The nanopipette was then incubated with a labeling DNA (HP2) and reporter 4-MBA-modified Raman tag. The Raman signal (collected from the tip area near the orifice within 1 µm) showed a good response to the content variation of intracellular miRNA-21 under ES, and the proposed single-cell SERS detection platform provides a simple way to study intracellular substance change and evaluate cancer treatment outcomes.

Smart Ratiometric SERS Nanoprobe for Real-Time Monitoring Hydrogen Peroxide in Living Cells during NADH Treatment Associated with Ferroptosis.

Studying the oxidative stress, especially the reactive oxygen species (ROS) response of ferroptosis, is crucial for the diagnosis and treatment of cancer based on ferroptosis. However, reliable quantitative analysis of intracellular ROS in cancer treatment for drug screening is still a challenge. Herein, a superior ratiometric SERS nanoprobe was developed for in situ, real-time, and highly sensitive detection of content variation of H2O2 within living cells. The SERS nanoprobe was prepared by coassembly of the internal standard molecule p-mercaptobenzonitrile and the reporter molecule p-mercaptophenylboronic acid on the surface of gold nanoparticles, used for synergistic calibration and detection of H2O2, which enables reliable detection of the true content of intracellular H2O2 without the interference of other substances in cells. Based on the nanoprobe, we found that the level of intracellular H2O2 of cancer cells was increased after the nicotinamide adenine dinucleotide (NADH) treatment, with a dose-dependence to the concentration of NADH. High doses of NADH (above 20 mM) can induce cell death by means of ferroptosis associated with the level elevation of intracellular lipid hydroperoxides. This study highlights the potential of the SERS nanoprobe for tracking content variation of cellular H2O2 and understanding its roles in screening new anticancer drugs.

Machine Learning-Based Label-Free SERS Profiling of Exosomes for Accurate Fuzzy Diagnosis of Cancer and Dynamic Monitoring of Drug Therapeutic Processes.

Exosomes are a class of extracellular vesicles secreted by cells, which can be used as promising noninvasive biomarkers for the early diagnosis and treatment of diseases, especially cancer. However, due to the heterogeneity of exosomes, it remains a grand challenge to distinguish accurately and reliably exosomes from clinical samples. Herein, we achieve accurate fuzzy discrimination of exosomes from human serum samples for accurate diagnosis of breast cancer and cervical cancer through machine learning-based label-free surface-enhanced Raman spectroscopy (SERS), by using "hot spot" rich 3D plasmonic AuNPs nanomembranes as substrates. Due to the existence of some weak distinguishable SERS fingerprint signals and the high sensitivity of the method, the machine learning-based SERS analysis can precisely identify three (normal and cancerous) cell lines, two of which are different types of cancer cells, without specific labeling of biomarkers. The prediction accuracy based on the machine learning algorithm was up to 91.1% for the discrimination of different cell lines (H8, HeLa, and MCF-7 cell)-derived exosomes. Our model trained with SERS spectra of cell-derived exosomes could reach 93.3% prediction accuracy for clinical samples. Furthermore, the action mechanism of the chemotherapeutic process of MCF-7 cells can be revealed by dynamic monitoring of SERS profiling of the exosomes secreted. The method would be useful for noninvasive and accurate diagnosis and postoperative assessment of cancer or other diseases in the future.

Real-Time Evaluation of Adhesion Processes and Glucose Response of Cancer Cells onto Phenylboronic Acid-Functionalized Films Monitored by Quartz Crystal Microbalance with Dissipation.

Understanding the interactions between cancer cells and smart substrates is of great benefit to physiology and pathology. Herein, we successfully fabricated two phenylboronic acid (PBA)-functionalized films with different surface topographies using a PBA homopolymer (PBAH) and self-assembled nanoparticles (PBAS) via a layer-by-layer assembly technique. We used a quartz crystal microbalance with dissipation (QCM-D) to monitor the entire cell adhesion process and figured out the adhesion kinetics of HepG2 cells on the two PBA-functionalized films. As seen from the QCM-D data, the HepG2 cells displayed distinctly different adhesion behaviors on the two PBA-functionalized films (PBAS and PBAH films). The results showed that the PBAS film promoted cell adhesion and cell spreading owing to its specific physicochemical properties. Likewise, the slope changes in the D-f plots clearly revealed the evolution of the cell adhesion process, which could be classified into three stages during cell adhesion on the PBA-functionalized films. In addition, compared with the PBAH film, the PBAS film could also control cell detachment behavior in the presence of glucose based on the molecular recognition between the PBA group and the cell membrane. Such a glucose-responsive PBAS film is promising for biological applications, including cell-based diagnostics and tissue engineering. In addition, the QCM-D proved to be a useful tool for in situ and real-time monitoring and analysis of interactions between cells and surfaces of supporting substrates.

Label-Free Single-Cell SERS Detection and Fluorescence Imaging of Molecular Responses to Endoplasmic Reticulum Stress under Electrical Stimulation.

The endoplasmic reticulum (ER) is one of the most important organelles in eukaryotic cells, in which most proteins and lipids are synthesized to regulate complex cellular processes. Generally, the excessive accumulation of unfolded or misfolded proteins can disturb ER homeostasis and induce endoplasmic reticulum stress (ERS). Howbeit, the molecular stress responses within ERS and metastatic behaviors of tumor cells during electrical stimulation (ES) are still poorly investigated and remain a challenge. In this study, by the combined use of fluorescence imaging, ER-targeting plasmonic nanoprobes were developed to trace molecular stress response profiling within the ER during a constant-voltage ES process at ∼1 V based on label-free surface-enhanced Raman spectroscopy (SERS). The excess accumulation of ß-misfolded proteins was found after the ES, leading to breaking of the ER homeostasis and further inducing mitochondrial dysfunction. Notably, the excessive stress of ER under ES can destroy the calcium ion balance and induce significant upregulation of calreticulin expression. Importantly, the content ratio of two kinds of cadherin between E-cadherin and N-cadherin was gradually improved with the voltages boosted. Meanwhile, the epithelial adhesion factor expression was ascended with voltages amplified, leading to inhibiting tumor cell migration at low voltages or death under higher voltages (∼1 V). This study provides cellular insights into the ES approach for tumor therapy and also provides a simple and effective method for detecting molecular stress responses in endoplasmic reticulum stress.

Solid-Phase Pyrolysis Synthesis of Highly Fluorescent Nitrogen/Sulfur Codoped Graphene Quantum Dots for Selective and Sensitive Diversity Detection of Cr(VI).

In this study, a simple one-step solid-phase pyrolysis synthesis procedure was employed to prepare N and S codoped highly fluorescent graphene quantum dots (N/S-GQDs). The as-synthesized quantum dot showed λexcitation-dependent blue fluorescence (FL) emission with a relative quantum yield of about 22% and displayed good biocompatibility, high water dispersibility, and excellent stability under extreme conditions (i.e., ionic strength, pH, and temperature). The potential applicability of the as-synthesized quantum dot was tested by employing solution- and paper-based FL detection modes for Cr(VI) detection. The proposed solution- and paper-based FL sensors showed lower limit of detection (LOD) values of 0.01 and 0.4 µM, respectively. The as-constructed paper- and solution-based FL sensors proved the feasibility of sensitive, cost-effective, and on-site detection of Cr(VI).

High-Entropy Oxide for Highly Efficient Luminol-Dissolved Oxygen Electrochemiluminescence and Biosensing Applications.

The luminol-dissolved O2 (DO) electrochemiluminescence (ECL) sensing system has recently gained growing interest; however, the drawback of the ultra-low ECL signal response greatly hinders its potential quantitative applications. In this work, for the first time, we explored the use of high entropy oxide (HEO) comprising five metal ingredients (Ni, Co, Cr, Cu, and Fe), to accelerate the reduction reaction of DO into reactive oxygen species (ROS) for boosting the ECL performance of the luminol-DO system. Benefiting from the existing abundant oxygen vacancies induced by the unique crystal structure of the HEO, DO could be efficiently converted into ROS, thus significantly boosting the performance of the corresponding ECL sensor (with an ∼240-fold signal enhancement in this study). As a proof of concept, under optimal conditions, the developed HEO-involved luminol-DO ECL sensing system was successfully applied for efficient biosensing of dopamine and alkaline phosphatase with a fine linear range from 1 pM to 10 nM and from 0.01 to 100 U/L as well as a low limit of detection of 5.2 pM and 0.008 U/L, respectively.

Glass Nanopore Detection of Copper Ions in Single Cells Based on Click Chemistry.

As a common redox metal ion pair in cells, copper ions (Cu2+/Cu+) often transform between oxidation (Cu2+) and reduction (Cu+) states. They play important roles in the redox process, so monitoring the change of intracellular copper ions helps understand the redox balance and events in cells. In this study, by self-assembling a thiolated ssDNA (with an alkyne end group) onto a gold-coated glass nanopore (G-nanopore) via the Au-S bond, an alkyne-end single-stranded DNA (ssDNA)-functionalized G-nanopore sensing platform (AG-nanopore) was developed to detect copper ions in cells. In the presence of Cu2+ or Cu+, the introduction of another ssDNA with an azide group will be ligated with an alkyne group on the functionalized nanopore via a copper-catalyzed azide-alkyne 1,3-cycloaddition (CuAAC) click reaction and hence cause the change of the rectification behavior of the AG-nanopore. The rectification ratio variation of the AG-nanopore had a good response to the intracellular copper ion concentration, and the sensing platform was further applied to the study of the relationship between intracellular oxidative stress and the value of Cu2+/Cu+.

Thermoplasmonic Regulation of the Mitochondrial Metabolic State for Promoting Directed Differentiation of Dental Pulp Stem Cells.

Regulating stem cell differentiation in a controllable way is significant for regeneration of tissues. Herein, we report a simple and highly efficient method for accelerating the stem cell differentiation of dental pulp stem cells (DPSCs) based on the synergy of the electromagnetic field and the photothermal (thermoplasmonic) effect of plasmonic nanoparticles. By simple laser irradiation at 50 mW/cm2 (10 min per day, totally for 5 days), the thermoplasmonic effect of Au nanoparticles (AuNPs) can effectively regulate mitochondrial metabolism to induce the increase of mitochondrial membrane potential and further drive energy increase during the DPSC differentiation process. The proposed method can specifically regulate DPSCs' cell differentiation toward odontoblasts, with the differentiation time reduced to only 5 days. Simultaneously, the molecular profiling change of mitochondria within DPSCs during the cell differentiation process is revealed by in situ surface-enhanced Raman spectroscopy. It clearly demonstrates that the expression of hydroxyproline and glutamate gradually increases with prolonging of the differentiation days. The developed method is simple, robust, and rapid for stem cell differentiation of DPSCs, which would be beneficial to tissue engineering and regenerative medicine.

Label-Free SERS Detection of Protein Damage in Organelles under Electrostimulation with 2D AuNPs-based Nanomembranes as Substrates.

Proteins as the material basis of life are the main undertakers of life activities. However, it is difficult to identify the related proteins in organelles during stimuli-induced stress responses in cells and remains a great challenge in early diagnosis and treatment of disease. Here, proteins in the cell nucleus and mitochondria of cells under the electrical stimulation (ES) process were collected and sensitively detected based on label-free surface-enhanced Raman spectroscopy (SERS) by using AuNP-based nanomembranes as high-performance SERS substrates. Due to the existence of rich "hot spots" on the 2D plasmonic sensing platform, high-quality SERS spectra of proteins were obtained with superior sensitivity and repeatability. From the SERS analyses in vitro, it was found that the conformation of some proteins in the two kinds of organelles from cancerous HCT-116 cells (compared with normal NCM-460 cells) changed significantly and the expression levels of tyrosine, phenylalanine, and tryptophan were significantly promoted during the stimulation process. Although currently the exact proteins are still unknown, the damage of proteins in the organelles of cells at the amino acid level under ES can be revealed by the method. The developed plasmonic SERS sensing platform would be promising for bioassay and cell studies.

Monitoring Stress Response Difference in Nucleolus Morphology and ATP Content Changes during Hyperthermia Cell Apoptosis with Plasmonic Fluorescent Nanoprobes.

The nucleolus, as a main "cellular stress receptor", is the hub of the stress response driving cancer development and has great research value in the field of organelle-targeting photothermal therapy. However, there are few studies focused on monitoring nucleolar stress response and revealing how the energy metabolism of cells regulates the nucleolar stress response during photothermal therapy. Herein, by designing a nucleolus-targeting and ATP- and photothermal-responsive plasmonic fluorescent nanoprobe (AuNRs-CDs) based on gold nanorods (AuNRs) and fluorescent carbon quantum dots (CDs), we achieved real-time fluorescence imaging of nucleus morphology while monitoring changes of ATP content at the subcellular level. We found that the green fluorescence diminished at 5 min of photothermal therapy, and the nucleolus morphology began to shrink and became smaller in cancerous HepG2 cells. In contrast, there is no significant change of green fluorescence in the nucleolar region of normal HL-7702 cells. ATP content monitoring also showed similar results. Apparently, in response to photothermal stimuli, cancerous cells produce more ATP (energy) along with obvious change in nucleolus morphology and state compared to normal cells under the hyperthermia-induced cell apoptosis. The developed AuNRs-CDs as a nucleolus imaging nanoprobe and effective photothermal agent present promising applications for nucleolar stress studies and targeted photothermal therapy.

Plasmon-Boosted Fe, Co Dual Single-Atom Catalysts for Ultrasensitive Luminol-Dissolved O2 Electrochemiluminescence Detection of Prostate-Specific Antigen.

Improving the sensitivity of electrochemiluminescence (ECL) systems is highly desired for in vitro ECL diagnosis and bio-detections due to the often-low content of biomarkers in diseases. And dissolved O2 (DO) as a co-reactant is considered superior to H2O2 in the most commonly used luminol ECL systems due to better stability and low biotoxicity, but it still suffers from low ECL performance due to the low reactivity of DO. In this study, an efficient luminol-DO ECL system was developed through the complexing of Fe, Co dual single-atom catalysts (D-SACs) supported by N-doped graphene with the luminol-capped Ag nanoparticles (AgNPs). Benefiting from the electronic interaction between Fe and Co metal sites in the relevant D-SACs and plasmon enhancement of AgNPs, the performance of the corresponding ECL system could be significantly boosted up to ≈677-fold under optimal testing conditions, comparable to the classic luminol-O2 system. Furthermore, the developed luminol-DO ECL system was successfully applied for the stable ultrasensitive detection of prostate-specific antigen (PSA) in a wide linear range of 1 fg/mL to 1 µg/mL, with a low limit of detection (0.98 fg/mL).

Plasmon-Enhanced Nitrogen Vacancy-Rich Carbon Nitride Electrochemiluminescence Aptasensor for Highly Sensitive Detection of miRNA.

The development of biosensors for biologically important substances with ultralow content such as microRNA is of great significance. Herein, a novel surface plasmon-enhanced electrogenerated chemiluminescence-based aptasensor was developed for ultrasensitive sensing of microRNA by using nitrogen vacancy-rich carbon nitride nanosheets as effective luminophores and gold nanoparticles as plasmonic sources. The introduction of nitrogen vacancies improved the electrochemiluminescence behavior due to improved conductance and electrogenerated chemiluminescence activity. The introduction of plasmonic gold nanoparticles increased the electrochemiluminescence signal intensity by more than eightfold. The developed surface plasmon-enhanced electrogenerated chemiluminescence aptasensor exhibited good selectivity, ultrasensitivity, excellent stability, and reproducibility for the determination of microRNA-133a, with a dynamic linear range of 1 aM to 100 pM and a limit of detection about 0.87 aM. Moreover, the surface plasmon-enhanced electrogenerated chemiluminescence sensor obtained a good recovery when detecting the content of microRNA in actual serum.

Optoplasmonic Modulation of Cell Metabolic State Promotes Rapid Cell Differentiation.

Cell differentiation plays a vital role in mediating organ formation and tissue repair and regeneration. Although rapid and effective methods to stimulate cell differentiation for clinical purposes are highly desired, it remains a great challenge in the medical fields. Herein, a highly effective and conceptual optical method was developed based on a plasmonic chip platform (made of 2D AuNPs nanomembranes). through effective light-augmented plasmonic regulation of cellular bioenergetics (CBE) and an entropy effect at bionano interfaces, to promote rapid cell differentiation. Compared with traditional methods, the developed optoplasmonic method greatly shortens cell differentiation time from usually more than 10 days to only about 3 days. Upon the optoplasmonic treatment of cells, the conformational and vibration entropy changes of cell membranes were clearly revealed through theoretical simulation and fingerprint spectra of cell membranes. Meanwhile, during the treatment process, bioenergetics levels of cells were elevated with increasing mitochondrial membrane potential (Δψm), which accelerates cell differentiation and proliferation. The developed optoplasmonic method is highly efficient and easy to implement, provides a new perspective and avenue for cell differentiation and proliferation, and has potential application prospects in accelerating tissue repair and regeneration.

Surface-Bonding-Enhanced Self-Co-Reactant Electrogenerated Chemiluminescence for Sensitive and Selective Detection of Thioglycolic Acid in Cosmetics.

Thioglycolic acid (TGA) is an organic compound widely used in cosmetics that cause a variety of health problems when overexposed to it. So far many attempts have been made to develop methods for TGA detection, but most of them need sophisticated instrumentations and are a little bit complicated. Therefore, a simple, cheap and sensitive detection method of TGA is highly desired. Herein, we demonstrated for the first time an Au-S bonding amplified, highly sensitive electrochemiluminescence (ECL) sensing method for TGA detection using tris(2,2'-bipyridyl)ruthenium(II) (Ru(bpy)3 2+ ) as a luminophore and TGA as a self-co-reactant, via an anodic reaction at the Au electrode surface. Due to different molecular coordination environments of the TGA at the electrode surface, the ECL signal intensity of the developed ECL system gives much higher ECL signal in borate buffer than phosphate buffer of the same pH. Under the optimized experimental conditions, the ECL intensity has a direct relationship with the concentration of TGA in the range of 0.03 µM to 300 µM and a limit of detection of 0.013 µM (3σ/m). The reported ECL system has further been applied for the detection of TGA in cosmetics with acceptable recoveries.

Smart Tumor Microenvironment-Responsive Nano-Prodrug for Disulfiram Toxification In Situ and the Exploration of Lethal Mechanisms in Cells.

Disulfiram (DSF) is a clinical antialcoholism drug that has been confirmed to show anticancer bioactivity after chelating with Cu2+. Therefore, how to co-deliver DSF and Cu2+ to tumor tissues and generate a smart response to the tumor microenvironment (TME) are the focus of repurposing DSF for the effective treatment of cancer. Herein, we fabricated facilely a smart nanosystem by coating tannic acid (TA) and Cu2+ network on DSF, denoted as DSF@TA-Cu, which responses well to TME and forms CuET complex in situ. In such a way, besides the chemotherapy effect of CuET, the anticancer efficacy of the resulting nano-prodrug can further be augmented by a continuous Fenton-like reaction. We then tested the cytotoxicity DSF@TA-Cu with normal and cancerous cell lines. Finally, by constructing mitochondria-targeted nanoprobes, we monitored the changes in mitochondrial metabolism and explored the lethal mechanisms in A549 cells. We found that DSF@TA-Cu showed higher toxicity to cancerous cells. By analyzing the fluorescence images and surface-enhanced Raman scattering (SERS) spectra of mitochondria, we found that the DNA damage and the decrease in mitochondrial membrane potential (MMP) were closely related to the generation and accumulation of reactive oxygen species (ROS). Although activated related pathways try to counteract the effects of elevation of ROS, excessive ROS inevitably leads to apoptosis of cancer cells.