H2S-driven chemotherapy and mild photothermal therapy induced mitochondrial reprogramming to promote cuproptosis.

The elevated level of hydrogen sulfide (H2S) in colon cancer hinders complete cure with a single therapy. However, excessive H2S also offers a treatment target. A multifunctional cascade bioreactor based on the H2S-responsive mesoporous Cu2Cl(OH)3-loaded hypoxic prodrug tirapazamine (TPZ), in which the outer layer was coated with hyaluronic acid (HA) to form TPZ@Cu2Cl(OH)3-HA (TCuH) nanoparticles (NPs), demonstrated a synergistic antitumor effect through combining the H2S-driven cuproptosis and mild photothermal therapy. The HA coating endowed the NPs with targeting delivery to enhance drug accumulation in the tumor tissue. The presence of both the high level of H2S and the near-infrared II (NIR II) irradiation achieved the in situ generation of photothermic agent copper sulfide (Cu9S8) from the TCuH, followed with the release of TPZ. The depletion of H2S stimulated consumption of oxygen, resulting in hypoxic state and mitochondrial reprogramming. The hypoxic state activated prodrug TPZ to activated TPZ (TPZ-ed) for chemotherapy in turn. Furthermore, the exacerbated hypoxia inhibited the synthesis of adenosine triphosphate, decreasing expression of heat shock proteins and subsequently improving the photothermal therapy. The enriched Cu2+ induced not only cuproptosis by promoting lipoacylated dihydrolipoamide S-acetyltransferase (DLAT) heteromerization but also performed chemodynamic therapy though catalyzing H2O2 to produce highly toxic hydroxyl radicals ·OH. Therefore, the nanoparticles TCuH offer a versatile platform to exert copper-related synergistic antitumor therapy.

Silver@Prussian Blue Core-Satellite Nanostructures as Multimetal Ions Switch for Potent Zero-Background SERS Bioimaging-Guided Chronic Wound Healing.

Metal-organic framework-based metal ion therapy has attracted increasing attention to promote the cascade wound-healing process. However, multimetal ion synergistic administration and accurately controlled ion release are still the challenges. Herein, an aptamer-functionalized silver@cupriferous Prussian blue (ACPA) is established as a metal-based theranostic nanoagent for a chronic nonhealing diabetic wound treatment. Prussian blue offers a programmable nanoplatform to formulate metal ion prescriptions, achieving cooperative wound healing. Silver, copper, and iron ions are released from ACPA controlled by the near-infrared-triggered mild hyperthermia and then synergistically participate in antipathogen, cell migration, and revascularization. ACPA also demonstrates a unique core-satellite nanostructure which enables it with improved surface-enhanced Raman scattering (SERS) capability as potent bacteria-targeted Raman-silent nanoprobe to monitor the residual bacteria during wound healing with nearly zero background. The theranostic feature of ACPA allows high-performance SERS imaging-guided chronic wound healing in infectious diabetic skin and keratitis.

NIR-II Responsive Molybdenum Dioxide Nanosystem Manipulating Cellular Immunogenicity for Enhanced Tumor Photoimmunotherapy.

Photothermal therapy (PTT) in the second near-infrared (NIR-II) window has emerged as a better candidate for deep-tissue tumor elimination. More interestingly, the photothermal ablated tumor cells also manifest somewhat immunostimulation potency to elicit antitumor immunity, although most dying cells are undergoing apoptosis that is commonly considered as immunologically silent. Here, a NIR-II responsive nanosystem is established for tumor photoimmunotherapy using molybdenum dioxide (MoO2) nanodumbbells as the nanoconverter. Meanwhile, an apoptosis-blocking strategy is proposed to regulate the cell death pattern under NIR-II laser irradiation in order to improve the immunogenic cell death. The nanoformulation can efficiently block caspase 8-dependent apoptotic pathway in photothermal ablated tumor cells and transform into more immunogenic death patterns, thereby activating systemic immunity to inhibit tumor growth and metastasis. In addition, this strategy also helps enhance the body's responses to α-PD-1 immune checkpoint inhibitor, which implies a potential optimal combination for cancer immunotherapy.

Facile synthesis of metal-phenolic-coated gold nanocuboids for surface-enhanced Raman scattering.

Metal-phenolic networks (MPNs) have been exploited to be a versatile coating film to fabricate core-shell structure due to their general adherent properties. Herein, gold nanocuboid (GNCB) wrapped by MPNs (GNCB at MPNs) are prepared by a facile encapsulation method for surface-enhanced Raman scattering (SERS) analysis. The MPN coating not only reshapes the electric field distribution around the nanostructures but also allows the substrate to adsorb more analytes, both of which contribute to the superior SERS activity of GNCB at MPNs. The SERS signals induced by plasmonic nanostructures increase four- to sixfold after MPN coating, reaching a maximum Raman enhancement factor calculated to be 9.47×108. Moreover, the core-shell SERS substrate also demonstrates improved biocompatibility (∼fivefold increase) that facilitates the reliable SERS analysis of cancer cells and further diverse biomedical applications.

Tumor microenvironment activation amplify oxidative stress promoting tumor energy remodeling for mild photothermal therapy and cuproptosis.

Tumor metabolic reprogramming requires high levels of adenosine triphosphate (ATP) to maintain treatment resistance, which poses major challenges to chemotherapy and photothermal therapy. Especially, high levels of ATP promote copper ion efflux for limiting the curative effect of cuproptosis. Here, an H2S-responsive mesoporous Cu2Cl(OH)3-loading chemotherapeutic cisplatin (CDDP) was synthesized, and the final nanoparticle, CDDP@Cu2Cl(OH)3-CDs (CDCuCDs), was encapsulated by electrostatic action with carbon dots (CDs). CDCuCDs reacted with overproduction H2S in colon tumor to produce photothermic copper sulfide for photothermal therapy. CDDP was released by lysis to achieve chemotherapeutic effects. Importantly, CDDP elevated H2O2 levels in cells through a cascade reaction and continuously transforms H2O2 into highly cytotoxic •OH through chemodynamic therapy between H2O2 and Cu+, which enables nanoparticles to generate •OH and improve the chemotherapeutic efficacy. Highly toxic •OH disrupts mitochondrial homeostasis, prohibiting it from performing normal energy-supplying functions. Down-regulated ATP inhibits heat shock protein expression, which promotes the therapeutic effect of mild photothermal therapy and reduces the efflux of intracellular copper ions, thus improving the therapeutic effect of cuproptosis. Our research provides a potential therapeutic strategy using overproduction H2S responses in tumors, allowing tumor microenvironment-activated •OH nanogenerators to promote tumor energy remodeling for cancer treatment.

Histopathological characteristics of adenomyosis: structure and microstructure.

Adenomyosis is a benign uterine disease that pathologically shows endometrial glands and stroma in the myometrium. There are multiple lines of evidence that adenomyosis is associated with abnormal bleeding, painful menstruation, chronic pelvic pain, infertility, and spontaneous pregnancy loss. Pathologists have researched adenomyosis by studying tissue specimens from its first report more than 150 years ago, and differing viewpoints on its pathological alterations have been advanced. However, the gold standard histopathological definition of adenomyosis remains controversial to date. The diagnostic accuracy of adenomyosis has steadily increased due to the continual identification of unique molecular markers. This article provides a brief description of the pathological aspects of adenomyosis and discusses adenomyosis categorization based on histology. The clinical findings of uncommon adenomyosis are also presented to offer a thorough and detailed pathological profile. Furthermore, we describe the histological alterations in adenomyosis after medicinal therapy.

Chronic poor healing wounds of post cesarean scar diverticulum: Altered angiogenesis and immunobiology.

Cesarean section (CS) scar diverticula (CSD) is an important cause impede further fecundity, with rather complicated pathophysiologic mechanisms and unclear etiopathogenesis. In this study, we detect the influences of CSD on the pregnancy outcomes in in-vitro fertilization (IVF) or intra-cytoplasmic sperm injection (ICSI) embryo transfer (ET) cycles, and further explore the mechanisms involved based on histopathology and immunology differences in endometrium between CSD and vaginal birth (VB) women. The CS group had significantly lower CLBR compared to NCS group. Histopathological analysis showed that the higher prevalent of CE is accompanied by excessive fibroblast proliferation at the lower segment of uterus and significantly exaggerated vascular proliferation in situ. Intrauterine inflammatory cytokines including IL-1α, IL-1ß, IL-6, IL-8, TNF-α and SDF-1α were also increased in CSD group. The present data suggests impaired fecundity in CSD women undergoing IVF/ICSI treatment. Although the causal relationship is ambiguous, the potential mechanisms may involve persistent inflammatory response in the uterine cavity, active vascular proliferation accompanied with increased fibrosis which are responsible for poor chronic wound healing of CSD.

Interaction between Cervical Microbiota and Host Gene Regulation in Caesarean Section Scar Diverticulum.

Cesarean section scar diverticulum (CSD) has become a formidable obstacle preventing women receiving CS from reproducing. However, the pathogenesis of CSD remains unexplored. In this study, we characterized the cervical microbiota, metabolome, and endometrial transcriptome of women with CSD. Based on the 16s rRNA results of cervical microbes, the microbial diversity in the CSD group was higher than that in the control group. Lactobacillus were significantly decreased in the CSD group and were mutually exclusive with potentially harmful species (Sphingomonas, Sediminbacterium, and Ralstonia) abnormally elevated in CSD. The microbiota in the CSD group exhibited low activity in carbohydrate metabolism and high activity in fatty acid metabolism, as confirmed by the metabolomic data. The metabolomic characterization identified 6,130 metabolites, of which 34 were significantly different between the two groups. In the CSD group, N-(3-hydroxy-eicosanoid)-homoserine lactone and Ternatin were significantly increased, in addition to the marked decrease in fatty acids due to high consumption. N-(3-hydroxy-eicosanoyl)-homoserine lactone is a regulator that promotes abnormal apoptosis in a variety of cells, including epithelial cells and vascular endothelial cells. This abnormal apoptosis of endometrial epithelial cells and neovascularization was also reflected in the transcriptome of the endometrium surrounding the CSD. In the endometrial transcriptome data, the upregulated genes in the CSD group were active in negatively regulating the proliferation of blood vessel endothelial cells, endothelial cells, and epithelial cells. This alteration in the host's endometrium is most likely influenced by the abnormal microbiota, which appears to be confirmed in the results by integrating host transcriptome and microbiome data. For the first time, this study described the abnormal activity characteristics of microbiota and the mechanism of host-microbiota interaction in CSD. IMPORTANCE Cesarean section scar diverticulum (CSD) has become a formidable obstacle preventing women receiving CS from reproducing. In this study, we revealed that potentially harmful microbes do have adverse effects on the host endometrium. The mechanism of these adverse effects includes the inhibition of the activity of beneficial bacteria such as lactobacilli, consumption of protective metabolites of the endometrium, and also the production of harmful metabolites. In the present study, we elucidated the mechanism from the perspectives of microbial, metabolic, and host responses, providing an important rationale to design preventive and therapeutic strategies for CSD.

SERS analysis of carcinoma-associated fibroblasts in a tumor microenvironment based on targeted 2D nanosheets.

Carcinoma-associated fibroblasts (CAFs), one of the most important components of a tumor microenvironment (TME), play a significant role in the complex tumorigenesis process. Herein, the evolution of CAFs in TME is elaborately investigated by surface-enhanced Raman spectroscopy (SERS), a molecular fingerprint technique. Two-dimensional (2D) nanocomposites consisting of gold nanoparticles and a supramolecular "PCsheet" self-assembled between 2D nanosheets and oxidized phosphatidylcholine (PC) are fabricated as SERS-active probes to specifically recognize the CD36 receptor on the cytomembrane of the fibroblasts, a reliable landmark of CAF development. The 2D SERS substrates can also illuminate the fingerprint information around the CD36 protein with high detection sensitivity, which helps elucidate the biochemical component transition in the protein mini-domain during carcinoma progression. Visualized data are then supplied by label-free SERS imaging to exploit the distribution of biomolecules on the plasma membrane. In addition, the repressed expression of CD36 in TME is detected in lung metastasis tumor-bearing mice. This study based on the 2D SERS technique opens up an alternative avenue for unveiling carcinoma-associated molecular events.

Photo-induced synthesis of molybdenum oxide quantum dots for surface-enhanced Raman scattering and photothermal therapy.

By means of a simple and photo-induced method, four colors of molybdenum oxide quantum dots (MoOx QDs) have been synthesized, using Mo(CO)6 as the structural guiding agent and molybdenum source. The as-prepared MoOx QDs display diverse optical properties due to the different configurations of oxygen vacancies in various nanostructures. Among them, crystalline molybdenum dioxide (MoO2) with a deep blue color shows the most intense localized surface plasmon resonance effect in the near-infrared (NIR) region. The strong NIR absorption endows MoO2 QDs with a high photothermal conversion efficiency of 66.3%, enabling broad prospects as a photo-responsive nanoagent for photothermal therapy of cancer. Moreover, MoO2 QDs can also serve as a novel semiconductor substrate for ultrasensitive surface-enhanced Raman scattering (SERS) analysis of aromatic molecules, amino acids and antibiotics, with SERS performance comparable to that of noble metal-based substrates. The therapeutic applications of MoO2 QDs open up a new avenue for tumor nanomedicine.

Biodegradable Black Phosphorus-based Nanomaterials in Biomedicine: Theranostic Applications.

Ascribe to the unique two-dimensional planar nanostructure with exceptional physical and chemical properties, black phosphorous (BP) as the emerging inorganic twodimensional nanomaterial with high biocompatibility and degradability has been becoming one of the most promising materials of great potentials in biomedicine. The exfoliated BP sheets possess ultra-high surface area available for valid bio-conjugation and molecular loading for chemotherapy. Utilizing the intrinsic near-infrared optical absorbance, BPbased photothermal therapy in vivo, photodynamic therapy and biomedical imaging has been realized, achieving unprecedented anti-tumor therapeutic efficacy in animal experiments. Additionally, the BP nanosheets can strongly react with oxygen and water, and finally degrade to non-toxic phosphate and phosphonate in the aqueous solution. This manuscript aimed to summarize the preliminary progresses on theranostic application of BP and its derivatives black phosphorus quantum dots (BPQDs), and discussed the prospects and the state-of-art unsolved critical issues of using BP-based material for theranostic applications.

Phase-controlled synthesis of molybdenum oxide nanoparticles for surface enhanced Raman scattering and photothermal therapy.

Different from their bulk counterparts, plasmonic molybdenum oxide nanomaterials display superior optical and electronic properties, but unfortunately, phase-controlled synthesis of molybdenum oxide nanomaterials with multifunctional performances still remains a challenge. To actualize this, a surfactant-free solvothermal strategy was proposed to fabricate molybdenum oxide nanomaterials with a tunable phase. Encouragingly, the as-prepared molybdenum dioxide nanoparticles (MoO2 NPs) exhibit intense near-infrared (NIR) absorption attributed to the localized surface plasmon resonance (LSPR) effect, which results in their application as a surface enhanced Raman scattering (SERS) substrate to detect trace amounts of molecular species including Rhodamine 6G (R6G), crystal violet (CV), IR-780 iodide (IR780) and methylene blue (MB). The detection limit was as low as 5 × 10-8 M and the maximum enhancement factor (EF) was up to 1.10 × 107, compared to other semiconductor nanostructures, the SERS sensitivity may be the best. Meanwhile, with the significant photothermal conversion efficiency up to 61.3%, the plasmonic MoO2 NPs could also be used as a photothermal therapy (PTT) agent for efficient photothermal ablation of cancer cells in vitro.

Multifunctional Nanoplatform Based on Black Phosphorus Quantum Dots for Bioimaging and Photodynamic/Photothermal Synergistic Cancer Therapy.

A multifunctional nanoplatform based on black phosphorus quantum dots (BPQDs) was developed for cancer bioimaging and combined photothermal therapy (PTT) and photodynamic therapy (PDT). BPQDs were functionalized with PEG chains to achieve improved biocompatibility and physiological stability. The as-prepared nanoparticles exhibite prominent near-infrared (NIR) photothermal and red-light-triggered photodynamic properties. The combined therapeutic application of PEGylated BPQDs were then performed in vitro and in vivo. The results demonstrate that the combined phototherapy significantly promote the therapeutic efficacy of cancer treatment in comparison with PTT or PDT alone. BPQDs could also serve as the loading platform for fluorescent molecules, allowing reliable imaging of cancer cells. In addition, the low cytotoxicity and negligible side effects to main organs were observed in toxicity experiments. The theranostic characteristics of PEGylated BPQDs provide an uplifting potential for the future clinical applications.