Novel PdPtCu Nanozymes for Reprogramming Tumor Microenvironment to Boost Immunotherapy Through Endoplasmic Reticulum Stress and Blocking IDO-Mediated Immune Escape.

Breaking immunosuppressive tumor microenvironment (TME) has unique effects on inhibiting tumor growth and recurrence. Here, an endoplasmic reticulum (ER) targeted PdPtCu nanozyme (PNBCTER ) is prepared to boost immunotherapy. First, PNBCTER has three kinds of enzyme activities, including catalase (CAT), glutathione oxidase (GSHOx), and peroxidase (POD)-like activities, which can reshape the TME. Second, PNBCTER kills tumor cells by photodynamic therapy (PDT) and photothermal therapy (PTT). Third, guided by TER , PNBCTER not only realizes the combination therapy of PDT, PTT and chemodynamic therapy (CDT), but also damages the ER of tumor cells and actives antitumor immune response, which breaks through the immune blockade of TME. Finally, the NLG919 blocks the tryptophan/kynurenine immune escape pathway and reverses the immunosuppressive TME. The strategy that reshaping the TME by enzyme catalysis and breaking immunosuppression provides a novel way for the application of combination therapy in tumor.

Characteristics of cathepsin members and expression responses to poly I:C challenge in Pacific cod (Gadus macrocephalus).

Cathepsins are major lysosomal enzymes that participate in necessary physiological processes, including protein degradation, tissue differentiation, and innate or adaptive immune responses. According to their proteolytic activity, vertebrate cathepsins are classified as cysteine proteases (cathepsins B, C, F, H, K, L, O, S, V, W, and X or Z), aspartic proteases (cathepsin D and E), and serine proteases (cathepsin A and G). Several cathepsins were reported in teleosts, however, no cathepsin gene has been identified from Pacific cod so far. In the present study, a total of 13 cathepsin genes were identified for Pacific cod. The evolutionary path of each cathepsin gene was demonstrated via analysis of phylogenetic trees, multiple alignments, conserved domains, motif compositions, and tertiary structures. Tissue distribution analysis showed that all cathepsin genes were ubiquitously expressed in eight healthy tissues but they exhibited diverse levels of expression. Several cathepsin genes were found to be highly expressed in the kidney, spleen, head kidney and liver, whereas low or modest levels were detected in the gills, skin, intestines, and heart. Temporal-specific expression of cathepsins in early developmental stages of Pacific cod were also conducted. CTSK, S, F, and Z were highly expressed at 1 dph and 5 dph and decreased later, while CTSL, L1, and L.1 transcript levels gradually increased in a time-dependent manner. Additionally, the expression profiles of cathepsin genes in Pacific cod were evaluated in the spleen and liver after poly I:C challenge. The results indicated that all cathepsin genes were significantly upregulated upon poly I:C stimulation, suggesting that they play key roles in antiviral immune responses in Pacific cod. Our findings establish a foundation for future exploration of the molecular mechanisms of cathepsins in modulating antiviral immunity in Pacific cod.

Differential response to topical lubrication in patient with dry eye disease, based on age.

BACKGROUND: To compare the Ocular surface disease index (OSDI) score, Schirmer I test (SIT), fluorescein break up time (FBUT) and fluorescence staining (FLCS) score of dry eye patients at different ages. METHODS: 90 eyes of 90 patients with mild to moderate dry eye from September 2020 to September 2021 were retrospectively included and were divided into young group (20-39 years, n = 29), middle-age group (40-59 years, n = 30), and elder group (> 60 years, n = 31). Patients were given a 28-day topical lubricating ocular surface and repair-promoting drugs combined with local physical therapy. Patients were followed up at 7, 14 and 28 days. The OSDI score, SIT, FBUT and FLCS score were examined. RESULTS: There were differences between the OSDI score in three groups at each time point (all P < 0.001). SIT were different among the three groups (F = 350.61, P < 0.001), and a time effect was found (F = 80.87, P < 0.001). SIT at 14 and 28 days after treatment in middle-age and elder groups were lower than young group (all P < 0.001). SIT at 7, 14 and 28 days in elder group were lower than middle-age group (all P < 0.001). FLCS score was lower at 28 days than other time points (all P < 0.001). CONCLUSION: Dry eye patients are given a 28-day topical lubricating ocular surface and repair-promoting drugs combined with local physical therapy, which can promote tear secretion, film stability, and the recovery of corneal integrity. Age affects the treatment effect of mild to moderate dry eye, among which tear secretion is the most significant.

The effect of loteprednol suspension eye drops after corneal transplantation.

BACKGROUND: To compare the effect of loteprednol suspension eye drops after corneal transplantation with the effect of prednisolone acetate eye drops. METHODS: A total of 234 patients (234 eyes) who underwent penetrating keratoplasty (PKP) and lamellar keratoplasty (LKP) were retrospectively included. Patients who received 1 % prednisolone acetate eye drops were defined as 1 % prednisolone acetate eye drop group (n = 96), and patients who received 0.5 % loteprednol suspension eye drops were defined as 0.5 % loteprednol suspension eye drop group (n = 138). RESULTS: 35 cases in 1 % prednisolone acetate eye drops group and 27 cases in 0.5 % loteprednol suspension eye drops group developed corticosteroid-induced ocular hypertension, and were defined as prednisolone acetate group and loteprednol group. No significant differences were observed in the average intraocular pressure (IOP) at 1 week, 1 month, 3 months or 12 months postoperatively. There were significant differences in the average IOP between the two groups at 6 months postoperatively (P = 0.001). There were no significant differences in the average best corrected visual acuity (BCVA) at 1, 3 and 12 months postoperatively between two groups. The average 6-month postoperative BCVA was significantly higher in the prednisolone acetate group than the loteprednol group (P < 0.05). There were no significant differences in the postoperative graft rejection rates between the two groups (P > 0.05). CONCLUSIONS: 0.5 % loteprednol suspension eye drops may be considered for long-term use after corneal transplantation.

Comparative Study on the Efficacy of Frozen Amniotic Membrane Transplantation and Lamellar Keratoplasty in the Treatment of Mooren Ulcer.

OBJECTIVE: To compare of the clinical efficacy of frozen amniotic membrane transplantation (AMT) and lamellar keratoplasty (LKP) in the treatment of Mooren ulcer. METHOD: Forty patients (42 eyes) with Mooren's ulcer in our hospital from January 2010 to January 2019 were divided into frozen AMT group (20 eyes) and LKP group (22 eyes). Comparative observation of post-operative best corrected visual acuity (BCVA), corneal epithelial healing time, corneal epithelialization time, ulcer healing, corneal transparency, corneal graft transparency, neovascularization and original disease recurrence were observed. RESULTS: The average BCVA at post-operative 6 and 12 months in LKP group were significantly lower than AMT group (P < 0.05). The ulcer healing rates in LKP group (63.6) were significantly higher than AMT group (30) (P < 0.05). The corneal epithelialization time of LKP group were 9.55 ±â€Š1.26 days. The corneal epithelial healing time of AMT group were 13.50 ±â€Š2.21 days. Nine cases were corneal graft transparency grade 0, and 13 cases were grade I. Three eyes in AMT group were corneal transparency grade 0, 7 were grade I and 10 were grade II. Corneal neovascularization were observed in 3 eyes in AMT group and 4 eyes in LKP group. The original disease recurrence rates in LKP group (50) were significantly higher than AMT group (20) (P < 0.05). Four cases of primary corneal transplantation failure were observed in LKP group. CONCLUSION: Lamellar keratoplasty group obtained significantly better BCVA during follow-up and faster healing time than the frozen AMT group while frozen AMT group had lower original disease recurrence rates than LKP group.

Comparison of the Clinical Efficacy of Boston Keratoprosthesis Type I and Repetitive Penetrating Keratoplasty for Refractory Keratopathy.

OBJECTIVE: To compare the clinical efficacy of Boston Keratoprosthesis type I (B-KProI) and penetrating keratoplasty (PKP) for patients with refractory keratopathy after 1failed PKP in China. METHOD: The 42 consecutive cases with refractory keratopathy after 1 failed PKP, from July 2010 to December 2014, were divided into 2 groups according to the surgical method: KPro group (n = 21) and PKP group (n = 21). Visual acuity (LogMAR), corneal graft transparency, postoperative complications and corneal graft survival rate were observed. The follow-up time was 2 years. The Kaplan-Meier curve was used to analyze the survival rate of the two groups of corneal grafts. RESULTS: The average best corrected visual acuity (BCVA) at 1, 6, 12, 18, and 24 months in KPro group were significantly lower than PKP group (P < 0.01). The best postoperative visual acuity and BCVA at postoperative 2 years in KPro group were lower than PKP group. The success rate of KPro group (86%) were significantly higher than PKP group (43%) (P < 0.01). There were no significant differences in indicate of complications in 2 groups including secondary glaucoma, secondary infectious corneal ulcer, corneal graft melting and endophthalmitis (P > 0.05). CONCLUSION: Compared with repetitive PKP, B-KProI had a higher success rate, improved postoperative visual acuity, reduced postoperative corneal transplant rejection rates and improved corneal graft survival rate.

Diversity and Abundance of the Denitrifying Microbiota in the Sediment of Eastern China Marginal Seas and the Impact of Environmental Factors.

Investigating the environmental influence on the community composition and abundance of denitrifiers in marine sediment ecosystem is essential for understanding of the ecosystem-level controls on the biogeochemical process of denitrification. In the present study, nirK-harboring denitrifying communities in different mud deposit zones of eastern China marginal seas (ECMS) were investigated via clone library analysis. The abundance of three functional genes affiliated with denitrification (narG, nirK, nosZ) was assessed by fluorescent quantitative PCR. The nirK-harboring microbiota were dominated by a few operational taxonomic units (OTUs), which were widely distributed in different sites with each site harboring their unique phylotypes. The mean abundance of nirK was significantly higher than that of narG and nosZ genes, and the abundance of narG was higher than that of nosZ. The inconsistent abundance profile of different functional genes along the process of denitrification might indicate that nitrite reduction occurred independently of denitrification in the mud deposit zones of ECMS, and sedimentary denitrification was accomplished by cooperation of different denitrifying species rather than a single species. Such important information would be missed when targeting only a single denitrifying functional gene. Analysis of correlation between abundance ratios and environmental factors revealed that the response of denitrifiers to environmental factors was not invariable in different mud deposit zones. Our results suggested that a comprehensive analysis of different denitrifying functional genes may gain more information about the dynamics of denitrifying microbiota in marine sediments.

Loss of NHE8 expression impairs ocular surface function in mice.

Sodium/hydrogen exchanger (NHE) 8 is expressed at the apical membrane of the epithelial cells and plays important roles in neutral sodium absorption in the gastrointestinal tract and the kidney. It also has an important role in epithelial mucosal protection in the gastric gland and the intestine. Although NHE8 has broad tissue distribution, the precise location and the physiological role of NHE8 in the eye remain unknown. In the present study, we successfully detected the expression of NHE8 in the ocular surface by PCR and Western blot in human and mouse eyes. Immunohistochemistry staining located NHE8 protein at the plasma membrane of the epithelial cells in the conjunctiva, the cornea, and the lacrimal gland both in human and mouse. We also detected the expression of downregulated-in-adenoma (DRA, a Cl(-)/HCO3 (-) transporter) in the ocular surface epithelial cells. Using NHE8-/- mouse model, we found that loss of NHE8 function resulted in reduced tear production and increased corneal staining. These NHE8-/- mice also showed increased expression of TNF-α and matrix metalloproteinase 9 (MMP9) genes. The expression of epithelial keratinization marker genes, small proline-rich protein 2h (Sprr2h) and transglutaminase 1 (Tgm1), were also increased in NHE8-/- eyes. Furthermore, DRA expression in NHE8-/- mice was reduced in the conjunctiva, the cornea, and the lacrimal glands in association with a reduction in conjunctival mucosal pH. Altered ocular surface function and reduced epithelial DRA expression in NHE8-/- mice suggest that the role of NHE8 in ocular surface tissue involve in tear production and ocular epithelial protection. This study reveals a potential novel mechanism of dry eye condition involving abnormal NHE8 function.

Experimental study on cryotherapy for fungal corneal ulcer.

BACKGROUND: Fungal corneal ulcer is one of the major causes of visual impairment worldwide. Treatment of fungal corneal ulcer mainly depends on anti-fungal agents. In the current study, we developed an integrated combination therapy of cryotherapy and anti-fungal agents to facilitate effective treatment of fungal corneal ulcer. METHODS: Rabbit models of cornea infection were established using a combined method of intrastromal injection and keratoplasty. After treatment with cryotherapy and anti-fungal agents, scanning electron microscopy, transmission electron microscopy, and confocal microscopy were conducted to observe changes in microstructure in the rabbits. Periodic acid Schiff A and hematoxylin and eosin staining were used for detection of histological changes. RESULTS: Continuous scanning electron microscopy and transmission electron microscopy observations showed that cryothermal treatment inhibited growth of fungal mycelium by destroying fungal cellular structures. Typical cryotherapy was effective in curing fungal corneal ulcer. Different fungi showed different susceptibilities to treatment. The curative effect of Candida albicans was the best, while that of Aspergillus fumigates was the worst. CONCLUSIONS: Our study provides a novel method of a combination of cryotherapy and anti-fungal agents for treatment of fungal corneal ulcer. This treatment could help facilitate the practice of fungal keratitis treatment in the future.

Biofilm microenvironment-activated multimodal therapy nanoplatform for effective anti-bacterial treatment and wound healing.

Antimicrobial drug development faces challenges from bacterial resistance, biofilms, and excessive inflammation. Here, we design an intelligent nanoplatform utilizing mesoporous silica nanoparticles doped with copper ions for loading copper sulfide (DM/Cu2+-CuS). The mesoporous silica doped with tetrasulfide bonds responds to the biofilm microenvironment (BME), releasing Cu2+ions, CuS along with hydrogen sulfide (H2S) gas. The release of hydrogen sulfide within 72 h reached 793.5 µM, significantly higher than that observed with conventional small molecule donors. H2S induces macrophages polarization towards the M2 phenotype, reducing inflammation and synergistically accelerating endothelial cell proliferation and migration with Cu2+ions. In addition, H2S disrupts extracellular DNA within biofilms, synergistically photothermal enhanced peroxidase-like activity of CuS to effectively eradicate biofilms. Remarkably, DM-mediated consumption of endogenous glutathione enhances the anti-biofilm activity of H2S and improves oxygen species (ROS) destruction efficiency. The combination of photothermal therapy (PTT), chemodynamic therapy (CDT), and gas treatment achieves sterilization rates of 99.3 % and 99.6 % against Staphylococcus aureus (S. aureus) and Escherichia coli (E. coli), respectively, in vitro under 808 nm laser irradiation. Additionally, in vivo experiments demonstrate a significant biosafety and antibacterial potential. In summary, the H2S donor developed in this study exhibits enhanced biocompatibility and controlled release properties. By integrating BME-responsive gas therapy with antibacterial ions, PTT and CDT, a synergistic multimodal strategy is proposed to offer new therapeutic approaches for wound healing. STATEMENT OF SIGNIFICANCE: The advanced DMOS/Cu2+-CuS (DMCC) multimodal therapeutic nanoplatform has been developed for the treatment of drug-resistant bacterial wound infections and has exhibited enhanced therapeutic efficacy through the synergistic effects of photothermal therapy, chemodynamic therapy, Cu2+ions, and H2S. The DMCC exhibited exceptional biocompatibility and could release CuS, Cu2+, and H2S in response to elevated concentrations of glutathione within the biofilm microenvironment. H2S effectively disrupted the biofilm structure. Meanwhile, peroxidase activity of CuS combined with GSH-mediated reduction of Cu2+ to Cu+ generated abundant hydroxyl radicals under acidic conditions, leading to efficient eradication of pathogenic bacteria. Furthermore, both H2S and Cu2+ could modulate M2 macrophages polarization and regulate immune microenvironment dynamics. These strategies collectively provided a novel approach for developing antibacterial nanomedical platforms.

Wet bio-amniotic membrane plugging combined with transplantation in the treatment of small corneal perforations.

PURPOSE: Wet bio-amniotic membrane plugging combined with transplantation is a novel option that combined amniotic membrane plugging with amniotic membrane transplantation for the treatment of small corneal perforations. This study aimed to evaluate the efficacy of wet bio-amniotic membrane plugging in the treatment of small corneal perforations and compared it with that of the penetrating keratoplasty procedure. METHODS: Forty patients (41 eyes) with small corneal perforations <3 mm in diameter treated at our hospital between July 2018 and January 2021 were retrospectively included. Among them, 21 eyes were treated with wet bio-amniotic membrane plugging (wet bio-amniotic membrane plugging group), and 20 eyes were treated with penetrating keratoplasty procedure (penetrating keratoplasty procedure group). The best-corrected visual acuity, anterior chamber formation, corneal thickness, primary disease control, postoperative complications, and graft survival rate were assessed. RESULTS: No significant difference in baseline characteristics was found between the wet bio-amniotic membrane plugging and penetrating keratoplasty procedure groups (p>0.05). The postoperative control rates of primary diseases in the wet bio-amniotic membrane plugging and penetrating keratoplasty procedure groups were 95.2% and 90.0%, respectively (p=0.481). Visual acuity was improved 6 months after the operation in the wet bio-amniotic membrane plugging group and was improved at postoperative 1 month in the penetrating keratoplasty procedure group. The formation time of the anterior chamber in the wet bio-amniotic membrane plugging group was significantly shorter than that in the penetrating keratoplasty procedure group (p=0.023). The corneal thickness of the two groups significantly increased 12 months after the operation; however, the degree of thickening in the penetrating keratoplasty procedure group was higher than that in the wet bio-amniotic membrane plugging group (p<0.001). During the follow-up, postoperative complications were not different between the two groups (p>0.999). CONCLUSION: The results suggest that wet bio-amniotic membrane plugging is effective and safe in the treatment of small corneal perforations. Thus, it can be used as an emergency treatment alternative to penetrating keratoplasty procedure for small corneal perforations.

The effect of cultured autologous oral mucosal epithelial cells on ocular surface reconstruction.

Introduction: Oral epithelial cells were recently shown to be able to differentiate into corneal epithelium, and the efficacy of cultured autologous oral mucosal epithelial cells (CAOMEC) has been suggested by the presence of epithelium replacement. Therefore, the aim of this study was to evaluate the treatment outcome in limbal stem cell deficiency (LSCD) by adding CAOMEC to regular amniotic membrane (AM) treatment. Material and methods: Eyes with LSCD were randomized to two groups to undergo either autologous oral mucosal epithelial cell sheet (CAOMECS) combined with AM transplantation (A group) or AM transplantation alone (B group). Clinical outcome measures were corneal epithelium healing, best corrected visual acuity, symblepharon, corneal transparency, corneal neovascularization and ocular surface inflammation. Results: The normal corneal epithelialization rate in group A (73.33%) was higher than that in group B (35.48%), and the average healing time was shorter (3.45 ±2.12 weeks vs. 4.64 ±1.63 weeks). The symblepharon in the above two groups was improved in the first 3 months after surgery, but after 6 months, part of the B group had recurrence. In improving corneal transparency, group A has obvious advantages. Corneal neovascularization (CNV) was improved to some extent in the first 3 months after surgery, but group A (1.47 ±0.64) was better than group B (1.94 ±0.85) after 6 months. Both groups can improve the inflammatory state to some extent. Conclusions: The transplantation of CAOMECS offers a viable and safe alternative in the reconstruction of a stable ocular surface. The effect is better than that of traditional AM transplantation, mainly in promoting corneal epithelialization, improving ocular surface structure, and reducing fiber and vascular infiltration.

Near-Infrared Light-Triggered Thermoresponsive Pyroptosis System for Synergistic Tumor Immunotherapy.

Pyroptosis, as an inflammatory cell death, has been widely applied in tumor therapy, but its systemic adverse reactions caused by nonspecific activation still seriously hinder its application. Herein, a near-infrared (NIR) light-triggered thermoresponsive pyroptosis strategy is designed for on-demand initiation of pyroptosis and synergistic tumor immunotherapy. Specifically, glucose oxidase (GOx) loaded and heat-sensitive material p(OEOMA-co-MEMA) (PCM) modified mesoporous Pt nanoparticles (abbreviated as PCM Pt/GOx) are prepared as the mild-temperature triggered pyroptosis inducer. Pt nanoparticles can not only serve as nanozyme with catalase-like activity to promote GOx catalytic reaction, but also act as photothermal agent to achieve mild-temperature photothermal therapy (PTT) and thermoresponsive GOx release on-demand under the irradiation of NIR light, thereby activating and promoting pyroptosis. In vitro and in vivo experiments prove that NIR light-triggered thermoresponsive pyroptosis system exhibits excellent antitumor immunity activity as well as significantly inhibits tumor growth. The precise control of pyroptosis by NIR light as well as pyroptosis cooperated with mild-temperature PTT for synergistically attenuated tumor immunotherapy are reported for the first time. This work provides a new method to initiate pyroptosis on demand, which is of great significance for spatiotemporally controllable pyroptosis and immunotherapy.

Ultra-small Janus nanoparticle-induced activation of ferroptosis for synergistic tumor immunotherapy.

Ferroptosis induced by lipid peroxide (LPO) accumulation is an effective cell death pathway for cancer therapy. However, how to effectively induce ferroptosis at tumor sites and improve its therapeutic effectiveness remains challenging. Here, MnFe2O4@NaGdF4@NLG919@HA (MGNH) nanocomplex with tumor-specific targeting and TME response is constructed to overcome immunosuppressive tumor microenvironment (TME) to potentiate the curative effect of ferroptosis by coupling the immune checkpoint indoleamine 2,3-dioxygenase (IDO) inhibitor, NLG919, and hyaluronic acid (HA) to novel ultra-small MnFe2O4@NaGdF4 (MG) nanoparticles with a Janus structure. Firstly, tumor site-precise delivery of MG and NLG919 is achieved with HA targeting. Secondly, MG acts as a magnetic resonance imaging contrast agent, which not only has a good photothermal effect to realize tumor photothermal therapy, but also depletes glutathione and catalyzes the production of reactive oxygen species from endogenous H2O2, which effectively promotes the accumulation of LPO and inhibits the expression of glutathione peroxidase 4, achieving enhanced ferroptosis. Thirdly, NLG919 inhibits the differentiation of Tregs by blocking the tryptophan/kynurenine immune escape pathway, thereby reversing immunosuppressive TME together with the Mn2+-activated cGAS-STING pathway. This work contributes new perspectives for the development of novel ultra-small Janus nanoparticles to reshape immunosuppressive TME and ferroptosis activation. STATEMENT OF SIGNIFICANCE: The Janus structured MnFe2O4@NaGdF4@NLG919@HA (MGNH) nanocomplex was synthesized, which can realize the precise delivery of T1/T2 contrast agents MnFe2O4@NaGdF4 (MG) and NLG919 at the tumor site under the ultra-small Janus structural characteristics and targeted molecule HA. The production of ROS, consumption of GSH, and photothermal properties of MGNH make it possible for CDT/PTT activated ferroptosis, and synergistically disrupt and reprogram tumor growth and immunosuppressive tumor microenvironment with NLG919 and Mn2+-mediated activation of cGAS-STING pathway, achieving CDT/PTT/immunotherapy activated by ferroptosis. Meanwhile, ultra-small structural properties of MGNH facilitate subsequent metabolic clearance by the body, allowing for the minimization of potential biotoxicity associated with its prolonged retention.

Fasting-Mimicking Diet Facilitates Anti-tumor Therapeutic Effects by Nutrient-Sensitive Nanocomposites.

Cancer cells support their uncontrolled proliferation primarily by regulating energy metabolism. Inhibiting tumor growth by blocking the supply of nutrients is an effective treatment strategy. Fasting-mimicking diet (FMD), as a low-calorie, low-protein, low-sugar, high-fat diet, can effectively reduce the nutrient supply to tumor cells. However, the significant biological barrier presented by the tumor microenvironment imposes greater demands and challenges for drug design. This study constructs the multifunctional nanocomposite ZnFe2O4@TiO2@CHC@Orl-FA (ZTCOF), which has great potential to overcome the aforementioned drawbacks. ZnFe2O4@TiO2 could produce 1O2 with ultrasound, and stimulate the Fenton-like conversion of endogenous H2O2 to ·OH, achieving a combined therapeutic effect of sonodynamic therapy (SDT) and chemodynamic therapy (CDT). Orl (Orlistat) and CHC (α-cyano-4-hydroxycinnamic acid) not only block tumor cell energy metabolism but also increase sensitivity to reactive oxygen species, enhancing the cytotoxic effect on tumor cells. Furthermore, combining the treatment strategies with FMD condition control can further inhibit cancer cell energy metabolism, achieving significant synergistic anti-tumor therapy. Both in vitro and in vivo experiments confirm that ZTCOF with SDT/CDT/starvation can achieve effective tumor suppression and destruction. This work provides theoretical and technical support for anti-tumor multimodal synergistic therapy.

Tumor Microenvironment-Specific Driven Nanoagents for Synergistic Mitochondria Damage-Related Immunogenic Cell Death and Alleviated Immunosuppression.

Despite significant breakthroughs in immunotherapy, the limitations of inadequate immune stimulation and stubborn immune resistance continue to present opportunities and challenges. Therefore, a two-pronged approach, encompassing the activation of immunogenic cell death (ICD) and blocking the indoleamine 2,3-dioxygenase (IDO)-mediated pathway, is devised to elicit systemic anti-tumor immunity and alleviate immunosuppression. Herein, a tumor microenvironment (TME)-specific driven nanoagent is composed of a tetrasulfide bond-bridged mesoporous silica layer (MON) coated up-conversion nanoparticles as a nano-carrier, combines Fe2+, curcumin, and indoximod for operating chemodynamic therapy/chemotherapy/immunotherapy. The consumption of glutathione (GSH) caused by MON degradation, the Fenton reaction of Fe2+, and curcumin triggering mitochondrial damage collectively exacerbate the oxidative stress, leading to a violent immunoreaction and reversal of the immunosuppressive TME through a combination of IDO-inhibitors. Meanwhile, upconversion luminescence (UCL) imaging serves as a significant guiding tool for drug delivery and the treatment of nanoagents. In vivo and in vitro experiment results demonstrate that the nanosystem not only effectively inhibits the growth of primary tumors but also induces immune priming and memory effects to reject re-challenged tumors. The strategy as a complementary approach displays great potential for future immunotherapy along with other multimodal treatment modes.

Rationally Integrated Precise ER-Targeted and Oxygen-Compensated Photodynamic Immunostimulant for Immunogenicity-Boosted Tumor Therapy.

Notwithstanding that immunotherapy has made eminent clinical breakthroughs, activating the immunogenicity and breaking the immunosuppressive tumor microenvironment (ITME) remains tempting yet challenging. Herein, a customized-designed immunostimulant is engineered for attenuating ITME and eliciting an immune response to address this challenge head-on. This immunostimulant is equipped with dual silica layers coated upconversion nanoparticles (UCNPs) as nanocarriers modified with endoplasmic reticulum (ER)-targeted molecular N-p-Tosylglycine, in which the dense silica for chlorin e6 (Ce6) and the glutathione (GSH)-responsive degradable silica for loading resveratrol (RES) - (UCSMRER ). On the one hand, this precise ER-targeted photodynamic therapy (PDT) can generate reactive oxygen species (ROS) in situ under the 980 nm laser irradiation, which not only induced severe cell death directly but also caused intense ER stress-based immunogenic cell death (ICD). On the other hand, tumor hypoxia aggravated by the PDT is alleviated by RES released on-demand, which reduced oxygen consumption by impairing the mitochondrial electron transport chain (ETC). This integrated precise ER-targeted and oxygen-compensated strategy maximized the PDT effect and potentiated ICD-associated immunotherapy, which availed to attenuate ITME, activate tumor immunogenicity, and further magnify the anti-tumor effect. This innovative concept about PDT and immunotherapy sheds light on cancer-related clinical application.

A "Chase and Block" Strategy for Enhanced Cancer Therapy with Hypoxia-Promoted Photodynamic Therapy and Autophagy Inhibition Based on Upconversion Nanocomposites.

The combination of hypoxia-promoted photodynamic therapy (PDT) and autophagy modulation has shown strong potential in the treatment of hypoxic tumors. Here, a novel design is put forward for synergistic PDT and autophagy inhibition to amplify the effect of cancer therapy by a "chase and block" strategy. Specifically, the organic photosensitive molecule (denoted FL) is encapsulated in a hydrophobic layer between multi-band emitted upconversion nanoparticles (UCNPs) and the amphiphilic polymer DSPE-PEG-COOH, allowing FL to fully exploit the luminescence spectrum of UCNPs under near-infrared (NIR) light irradiation. The FL is specifically activated by nitroreductase in the tumor microenvironment (TME), enabling hypoxia-promoted PDT and thus performing a "chase" strategy for cancer therapy. Additionally, the nanosystem is combined with an autophagy-inhibiting melittin pro-peptide (denoted as MEL), which could be triggered by the highly expressed legumain in tumor cells to inhibit the autophagy procedure by disrupting the lysosomal membrane, thus "blocking" the cancer cells from rescuing themselves and amplifying the killing effect of PDT. Both FL and MEL can be specifically activated by TME and the upconversion luminescence imaging of UCNPs offers a tracer function for the treatment. Therefore, UCNPs@FL-MEL might be an important reference for the design and development of future nanotherapeutic agents.

Construction of mPt/ICG-αA nanoparticles with enhanced phototherapeutic activities for multidrug-resistant bacterial eradication and wound healing.

The emergence of multidrug-resistant (MDR) bacterial infections calls for novel strategies for effective bacterial inhibition and wound healing. Phototherapeutic approaches are promising in treating bacterial infection because of their high efficiency, noninvasiveness, and few side effects; however, their antibacterial effect is limited by the formation of biofilms in wounds. Herein, we report novel composite nanoparticles (mPt/ICG-αA NPs) combining mesoporous platinum (mPt) nanoparticles, indocyanine green (ICG) and α-amylase (αA) for combating MDR bacteria and treating wound infection, which integrates a triple bacterial inhibition mechanism arising from the combination of photodynamic therapy (PDT), photothermal therapy (PTT) and α-amylase enzymatic activities. The combination of mPt and ICG significantly enhances the effect of PTT and the temperature can be increased up to 80.8 °C to induce efficacious bacterial degeneration. Meanwhile, mPt/ICG-αA (mPIA) NPs with a low concentration of 25 µg mL-1 exhibited a remarkable catalase activity (CAT) and could continuously decompose endogenous H2O2 into O2 in a hypoxic microenvironment, thereby enhancing the PDT effect to achieve broad-spectrum bactericidal activity. mPIA NPs showed excellent MDR antibacterial efficiency against both Gram-positive Staphylococcus aureus (S. aureus) and Gram-negative Escherichia coli (E. coli), and the bactericidal rate reached up to 99.0% and 97.2% with single 808 nm near-infrared light irradiation, respectively. mPIA NPs also exhibited an excellent ability to destroy biofilms and biocompatibility. Animal experiments further suggested that mPIA NPs could achieve the successful repairment of wounds infected with S. aureus in living systems, while this platform demonstrated negligible toxicity towards mice. Considering the superior performances of mPIA NPs, the synergistic αA-CAT-PDT-PTT boosted therapeutic activity presented in the current work provides a promising method to effectively fight against biofilm-related infectious diseases and wound healing.

[Morphologic changes in acute central serous chorioretinopathy evaluated by spectral domain optical coherence tomography].

OBJECTIVE: To describe the pathologic changes of macular in acute central serous chorioretinopathy (CSC) using spectral domain optical coherence tomography (SD-OCT). METHODS: It was a retrospective case series study. This study included 29 eyes of 29 patients with CSC. The fundus examination was conducted followed by SD-OCT to observe foveal microstructure changes. We evaluated the correlation between the thickness of the outer nuclear layer (ONL), the length of photoreceptors and best-corrected visual acuity (BCVA). RESULTS: Serous retinal detachment was found in all 29 eyes with SD-OCT. There was no obvious morphology change in ONL, the thickness of ONL was (96.94 ± 23.72) µm and did not different from that in normal control eyes (104.15 ± 11.90) µm. The thickness of photoreceptors was uniform in 11 eyes (31.9%), uniform but with defects in 6 eyes (20.7%), uneven in 4 eyes (13.8%), protruding of outer segments (OS) was observed in 6 eyes (20.7%) and flaking OS in 2 eyes (6.9%). The length from external limiting membrane to the longest outer segment in CSC eyes was 84 (52 to 148) µm and was not statistically different from that in normal eyes (69 to 82)µm. Morphology changes of retinal pigment epithelium (RPE) were found in 25 eyes, including pigment epithelial detachment of RPE (PED) in 21 eyes (72.4%), small bulge of RPE in 10 eyes (34.5%), granular deposition epi-RPE in 6 eyes (20.7%), defects of RPE in 3 eyes (10.3%). Fluorescein angiography (FA) was performed in 5 eyes and bulging RPE detected by SD-OCT seemed to correspond precisely to the leakage point on FA in 3 eyes. Age, course of disease and thickness of the ONL did not influence BCVA (logMAR). Uneven of thickness of OS was negative prognostic factors for BCVA (r = 0.382, P = 0.026). CONCLUSIONS: SD-OCT can demonstrate finer pathologic changes in acute CSC. Furthermore, 3-D image allows localization of these pathologic features to specific site using ELM line as landmark. SD-OCT is a valuable tool for the diagnosis and for predicting visual recovery in CSC.