Temperature-Tuning Desorption Ionization for Ambient Mass Spectrometry.

In the past decade, mass spectrometry (MS) has been widely used for a broad range of on-site applications. This is largely attributed to the rapid advancement of technologies, such as ambient ionization and mass spectrometer miniaturization. Here, we report the development of the temperature-tuning desorption ionization (TTDI) method for versatile on-site applications using a miniature MS system. A unique feature of TTDI is its dynamic temperature range applicable from 30 to 800 °C, which enables optimal desorption ionization applied for chemical and biological compounds through tuning the temperature at the sampling spot. The versatility of TTDI has been demonstrated through on-site MS analysis of a variety of samples, such as explosives on surfaces, drugs of abuse in biofluids, and screening biomarkers in tissues.

Biomimetic Nano-Immunoactivator via Ionic Metabolic Modulation for Strengthened NIR-II Photothermal Immunotherapy.

Reprogramming the immunologically "cold" environment of solid tumors is currently becoming the mainstream strategy to elicit powerful and systemic anticancer immunity. Here, a facile and biomimetic nano-immunnoactivator (CuS/Z@M4T1 ) is detailed by engineering a Zn2+ -bonded zeolitic imidazolate framework-8 (ZIF-8) with CuS nanodots (NDs) and cancer cell membrane for amplified near-infrared-II (NIR-II) photothermal immunotherapy via Zn2+ metabolic modulation. Taking advantage of the NIR-II photothermal effect of CuS NDs and the acidic responsiveness of ZIF-8, CuS/Z@M4T1 rapidly causes intracellular Zn2+ pool overload and disturbs the metabolic flux of 4T1 cells, which effectively hamper the production of heat shock proteins and relieve the resistance of photothermal therapy (PTT). Thus, amplified immunogenic cell death is evoked and initiates the immune cascade both in vivo and in vitro as demonstrated by dendritic cells maturation and T-cell infiltration. Further combination with antiprogrammed death 1 (aPD-1) achieves escalated antitumor efficacy which eliminates the primary, distant tumor and avidly inhibits lung metastasis due to cooperation of enhanced photothermal stimulation and empowerment of cytotoxic T lymphocytes by aPD-1. Collectively, this work provides the first report of using the intrinsic modulation property of meta-organometallic ZIF-8 for enhanced cancer photoimmunotherapy together with aPD-1, thereby inspiring a novel combined paradigm of ion-rich nanomaterials for cancer treatment.

miR-15a-5p up-regulates TLR4 and induces the formation of hypertrophic scars and keloids.

The formation of hypertrophic scar and keloid is considered to be a very complex pathological process. Our previous studies have shown that miR-15a-5p is an important miRNA in HTS tissues, and its expression level is significantly increased. Therefore, the potential mechanism of action of miR-15a-5p in scarring arouses our interest. This study preliminarily investigated the expression level of miR-15a-5p in HTS tissue and normal skin tissue and further explored the molecular mechanism. The results of this study once again confirmed that the expression level of miR-15a-5p was increased in HTS tissues and cells, and the closely related mRNA and protein levels of MyD88 and TGF-ß were also highly expressed. The relative expression levels of fibrosis-related indicators in HTsFb cells were up-regulated, such as collagen-Ⅰ, collagen-III and α-SMA. We constructed the HTS cell model and BALB/c nude animal model, and down-regulating miR-15a-5p, the HTsFb cells proliferation was inhibited, and qRT-PCR results showed that the fibrosis index mRNA was also reduced, and significantly reduce the pathological state of scar tissue. In conclusion, miR-15a-5p may participate in the formation and development of HTS through TLR/MyD88 signaling pathway and TGF-ß1 signaling pathway.

Simulation-based comparison of Biopharmaceutics Classification System and drug structure.

Background: The Biopharmaceutics Classification System (BCS), which classifies bioactive molecules based on solubility and permeability, is widely used to guide new drug development and drug formulation, as well as predict pharmacokinetics. Here we performed computer simulations to study correlations between a molecule's structure and its BCS classification. Methods: A total of 411 small molecules were assigned to BCS categories based on published drug data, and their Pybel-FP4 fingerprints were extrapolated. The information gain (IG) of each fingerprint was calculated and its characteristic structure analyzed. IG was calculated using multiple thresholds, and results were verified using support vector machine prediction, while taking into account the dose coefficient (0-0.1, 0.1-1, or >1). Structural functional features common to fingerprints of compounds in each type of BCS class were determined using computer simulations. Results: BCS classes III and IV appear to share several structural and functional characteristics, including secondary aliphaticamine, Michael acceptor, isothiourea, and sulfonamide sulfonic derivatives. Conclusion: We demonstrate that our approach can correlate characteristic fingerprints of small-molecule drugs with BCS classifications, which may help guide the development and optimization of new drugs.

Decreasing acute toxicity and suppressing colorectal carcinoma using Sorafenib-loaded nanoparticles.

Objective: A polymer-based nanoparticle was constructed to target sorafenib delivery to colorectal carcinoma cells and decrease the side effects of the drug.Methods: Sorafenib-loaded nanoparticles (S-NPs) based on PEG-PLGA were prepared using a double emulsion solvent evaporation method. The properties of S-NPs were evaluated and then their effects on the viability of colorectal cancer cells and normal human cells were assessed. The mechanism of S-NP internalization was explored using cellular uptake assays and in vitro fluorescence confocal imaging. Acute toxicity of sorafenib on its own or within S-NPs was assessed in mice.Results: S-NPs showed high drug loading and entrapment efficiencies, they did not cause extensive hemolysis, and they efficiently inhibited growth of colorectal cancer cell lines and human umbilical vein endothelial cells. S-NPs showed lower acute toxicity than the free drug.Conclusions: Loading sorafenib into nanoparticles can enhance its uptake by colorectal cancer cells and decrease its acute toxicity.

Thermo- and pH-responsive, Lipid-coated, Mesoporous Silica Nanoparticle-based Dual Drug Delivery System To Improve the Antitumor Effect of Hydrophobic Drugs.

Evodiamine (EVO) and Berberine (BBR), from Euodiae Fructus and Coptidis rhizoma, have been used as an herbal medicine pair in traditional Chinese medicine to exert synergistic antitumor effects against various types of tumor cells. However, their clinical use is limited by their poor solubility and adverse toxic side effects. Mesoporous silica nanoparticles (MSNs) possess excellent properties such as a readily functionalized surface, prominent biocompatibility, and huge specific surface area for loading with hydrophobic and hydrophilic drug. On this basis, a novel temperature- and pH-responsive dual drug delivery platform has been developed, in which lipid-coated MSN@p(NIPAM- co-MA) codelivers EVO and BBR. The results indicate that the nanocarrier improves the efficacy and biocompatibility of the drug pair and maintain desirable drug profiles at the low pH and higher temperature of the tumor microenvironment. The dual drug-loaded MSNs showed excellent synergistic therapy effects in vitro (cytotoxicity, cell migration and invasion, angiogenesis) and in vivo (growth of tumor grafts in mice). Meanwhile, the dual drug-loaded nanoparticles showed lower systemic toxicity than either drug alone, the free drug combination, or Taxol. These results suggest that the temperature- and pH-sensitive lipid-coated MSNs are a promising novel carrier for both hydrophobic and hydrophilic drugs.

Cyanidin-3-O-glucoside chloride acts synergistically with luteolin to inhibit the growth of colon and breast carcinoma cells.

In this study, we investigated whether the combination of cyanidin-3-O-glucoside chloride and luteolin could inhibit the growth of HCT-8 colon and MCF-7 breast carcinoma cells, and whether the effect of the combination was greater than the effect of either drug on its own. Growth inhibition was assessed using the CCK-8 assay, level of apoptosis and cell cycle distribution were determined using flow cytometry, and the mechanism of apoptosis induction was explored using a colorimetric assay of caspases-3 and -9. Experiments indicated that combination treatment inhibited proliferation and increased apoptosis in both cell lines to a greater extent than either drug on its own. These results suggest that luteolin and cyanidin-3-O-glucoside chloride synergistically inhibitthe growth of colon cancer and breast cancer cells. This work justifies further effort to develop this potential combination therapy.

Biomimetic "Gemini nanoimmunoregulators" orchestrated for boosted photoimmunotherapy by spatiotemporally modulating PD-L1 and tumor-associated macrophages.

A novel strategy of not only stimulating the immune cycle but also modulating the immunosuppressive tumor microenvironment is of vital importance to efficient cancer immunotherapy. Here, a new type of spatiotemporal biomimetic "Gemini nanoimmunoregulators" was engineered to activate robust systemic photoimmunotherapy by integrating the triple-punch of amplified immunogenic cell death (ICD), tumor-associated macrophages (TAMs) phenotype reprogramming and programmed cell death ligand 1 (PD-L1) degradation. The "Gemini nanoimmunoregulators" PM@RM-T7 and PR@RM-M2 were constructed by taking the biocompatible mesoporous polydopamine (mPDA) as nanovectors to deliver metformin (Met) and toll-like receptor 7/8 agonist resiquimod (R848) to cancer cells and TAMs by specific biorecognition via wrapping of red blood cell membrane (RM) inlaid with T7 or M2 peptides. mPDA/Met@RM-T7 (abbreviated as PM@RM-T7) was constructed to elicit an amplified in situ ICD effect through the targeted PTT and effectively stimulated the anticancer immunity. Meanwhile, PD-L1 on the remaining cancer cells was degraded by the burst metformin to prevent immune evasion. Subsequently, mPDA/R848@RM-M2 (abbreviated as PR@RM-M2) specifically recognized TAMs and reset the phenotype from M2 to M1 state, thus disrupting the immunosuppressive microenvironment and further boosting the function of cytotoxic T lymphocytes. This pair of sister nanoimmunoregulators cooperatively orchestrated the comprehensive anticancer activity, which remarkably inhibited the growth of primary and distant 4T1 tumors and prevented malignant metastasis. This study highlights the spatiotemporal cooperative modalities using multiple nanomedicines and provides a new paradigm for efficient cancer immunotherapy against metastatic-prone tumors.

Contextualizing Gender Disparity in Editorship in Psychological Science.

Discourse on gender diversity tends to overlook differences across levels of hierarchy (e.g., students, faculty, and editors) and critical dimensions (e.g., subdisciplines and geographical locations). Further ignored is its intersection with global diversity-representation from different countries. Here we document and contextualize gender disparity from perspectives of equal versus expected representation in journal editorship, by analyzing 68 top psychology journals in 10 subdisciplines. First, relative to ratios as students and faculty, women are underrepresented as editorial-board members (41%) and-unlike previous results based on one subfield-as editors-in-chief (34%) as well. Second, female ratios in editorship vary substantially across subdisciplines, genres of scholarship (higher in empirical and review journals than in method journals), continents/countries/regions (e.g., higher in North America than in Europe), and journal countries of origin (e.g., higher in American journals than in European journals). Third, under female (vs. male) editors-in-chief, women are much better represented as editorial-board members (47% vs. 36%), but the geographical diversity of editorial-board members and authorship decreases. These results reveal new local and broad contexts of gender diversity in editorship in psychology, with policy implications. Our approach also offers a methodological guideline for similar disparity research in other fields.

Global Diversity of Authors, Editors, and Journal Ownership Across Subdisciplines of Psychology: Current State and Policy Implications.

Diversity is the fuel of innovation. Global diversity-geographical or international diversification-is indispensable for developing a true psychological science of human beings but remains poorly understood. We surveyed 68 top psychology journals in 10 subdisciplines and examined the global diversity of authors, editors (i.e., members of academic editorial teams), and journal ownership. Results show that (a) the global diversity of authorship, editorship, and ownership is low in top psychology journals, with the United States boasting outsized influences; (b) disparity intensifies along the hierarchy of authors, editors, and journal ownership and substantially differs between subdisciplines and journal types; (c) removing the United States markedly increases global diversity and eliminates differences in diversity between subdisciplines and between authorship and editorship; and (d) more authors and editors are from the journal's home country (vs. a foreign journal) and from the editor-in-chief's home country (vs. a journal with a foreign editor-in-chief), and the home-country biases are most pronounced in the United States-journals from the United States or with U.S. editors-in-chief have the lowest global diversity in authorship and editorship. These results provide substantial novel insights into the global diversity of psychology journals, with implications for a new diversity policy to stimulate the generation of variety and, by extension, innovation.

NFAT5 Restricts Bovine Herpesvirus 1 Productive Infection in MDBK Cell Cultures.

Bovine herpesvirus 1 (BoHV-1), an important bovine viral pathogen, causes severe disease in the upper respiratory tract and reproductive system. Tonicity-responsive enhancer-binding protein (TonEBP), also known as nuclear factor of activated T cells 5 (NFAT5), is a pleiotropic stress protein involved in a range of cellular processes. In this study, we showed that the knockdown of NFAT5 by siRNA increased BoHV-1 productive infection and overexpression of NFAT5 via plasmid transfection decreased virus production in bovine kidney (MDBK) cells. Virus productive infection at later stages significantly increased transcription of NFAT5 but not appreciably alter measurable NFAT5 protein levels. Virus infection relocalized NFAT5 protein and decreased the cytosol accumulation. Importantly, we found a subset of NFAT5 resides in mitochondria, and virus infection led to the depletion of mitochondrial NFAT5. In addition to full-length NFAT5, another two isoforms with distinct molecular weights were exclusively detected in the nucleus, where the accumulation was differentially affected following virus infection. In addition, virus infection differentially altered mRNA levels of PGK1, SMIT, and BGT-1, the canonical downstream targets regulated by NFAT5. Taken together, NFAT5 is a potential host factor that restricts BoHV-1 productive infection, and virus infection hijacks NFAT5 signaling transduction by relocalization of NFAT5 molecules in cytoplasm, nucleus, and mitochondria, as well as altered expression of its downstream targets. IMPORTANCE Accumulating studies have revealed that NFAT5 regulates disease development due to infection of numerous viruses, underlying the importance of the host factor in virus pathogenesis. Here, we report that NFAT5 has capacity to restrict BoHV-1 productive infection in vitro. And virus productive infection at later stages may alter NFAT5 signaling pathway as observed by relocalization of NFAT5 protein, reduced accumulation of NFAT5 in cytosol, and differential expression of NFAT5 downstream targets. Importantly, for the first time, we found that a subset of NFAT5 resides in mitochondria, implying that NFAT5 may regulate mitochondrial functions, which will extend our knowledge on NFAT5 biological activities. Moreover, we found two NFAT5 isoforms with distinct molecular weights were exclusively detected in the nucleus, where the accumulation was differentially affected following virus infection, representing a novel regulation mechanism on NFAT5 function in response to BoHV-1infection.

A tumor-specific ROS self-supply enhanced cascade-responsive prodrug activation nanosystem for amplified chemotherapy against multidrug-resistant tumors.

Chemotherapy remains the mainstay of cancer treatment, and doxorubicin (DOX) is recommended as a first-line chemotherapy drug against cancer. However, systemic adverse drug reactions and multidrug resistance limit its clinical applications. Here, a tumor-specific reactive oxygen species (ROS) self-supply enhanced cascade responsive prodrug activation nanosystem (denoted as PPHI@B/L) was developed to optimize multidrug resistance tumor chemotherapy efficacy while minimizing the side effects. PPHI@B/L was constructed by encapsulating the ROS-generating agent ß-lapachone (Lap) and the ROS-responsive doxorubicin prodrug (BDOX) in acidic pH-sensitive heterogeneous nanomicelles. PPHI@B/L exhibited particle size decrease and charge increase when it reached the tumor microenvironment due to acid-triggered PEG detachment, to favor its endocytosis efficiency and deep tumor penetration. Furthermore, after PPHI@B/L internalization, rapidly released Lap was catalyzed by the overexpressed quinone oxidoreductase-1 (NQO1) enzyme NAD(P)H in tumor cells to selectively raise intracellular ROS levels. Subsequently, ROS generation further promoted the specific cascade activation of the prodrug BDOX to exert the chemotherapy effects. Simultaneously, Lap-induced ATP depletion reduced drug efflux, synergizing with increased intracellular DOX concentrations to assist in overcoming multidrug resistance. This tumor microenvironment-triggered cascade responsive prodrug activation nanosystem potentiates antitumor effects with satisfactory biosafety, breaking the chemotherapy limitation of multidrug resistance and significantly improving therapy efficiency. STATEMENT OF SIGNIFICANCE: Chemotherapy remains the mainstay of cancer treatment, and doxorubicin (DOX) is recommended as a first-line chemotherapy drug against cancer. However, systemic adverse drug reactions and multidrug resistance limit its clinical applications. Here, a tumor-specific reactive oxygen species (ROS) self-supply enhanced cascade responsive prodrug activation nanosystem (denoted as PPHI@B/L) was developed to optimize multidrug resistance tumor chemotherapy efficacy while minimizing the side effects. The work provides a new sight for simultaneously addressing the molecular mechanisms and physio-pathological disorders to overcome MDR in cancer treatment.

Corrigendum to "Remodeling tumor immunosuppressive microenvironment via a novel bioactive nanovaccines potentiates the efficacy of cancer immunotherapy" [Bioactive Mater. 16 107-119].

[This corrects the article DOI: 10.1016/j.bioactmat.2022.03.008.].

Co-encapsulation of paclitaxel and 5-fluorouracil in folic acid-modified, lipid-encapsulated hollow mesoporous silica nanoparticles for synergistic breast cancer treatment.

A dual-loaded multi-targeted drug delivery nanosystem was constructed to simultaneously load paclitaxel (PTX) and 5-fluorouracil (5-FU) for targeted delivery and sustained release at tumor sites. Hollow mesoporous silica nanoparticles (HMSNs) were prepared by the inverse microemulsion method, then modified with folic acid and pH- and temperature-responsive materials, co-loaded with PTX and 5-FU, and finally encapsulated into lipid membranes. The obtained nanosystem was selectively internalized by human breast cancer MCF-7 cells that overexpress folate receptors through an energy-dependent process, and it released both drugs in vitro in a simulated tumor microenvironment. Moreover, the inhibitory effect of the dual-loaded nanoparticles was significantly better than that of the free drugs, suggesting that the composite nanosystem has the potential to selectively target tumor sites and perform the synergistic effect of PTX and 5-FU, while reducing their toxic effects on normal tissues.

Tumor homing-penetrating and nanoenzyme-augmented 2D phototheranostics against hypoxic solid tumors.

Tumor microenvironment (TME)-oriented nanomedicine emerges as an efficient routine to greatly improve the efficiency of cancer treatment. The typical feature of hypoxia in TME remains as the main obstacle of many therapeutics like photodynamic therapy. Herein, a specific two-dimensional (2D) phototheranostics (GO-MnO2@tLyP-1/Ce6, denoted as GMtC) with the function of oxygen self-producing and tumor barrier-breaking was detailed by integrating the nanoenzyme MnO2 colloids, tumor homing-penetrating peptide tLyP-1 and photosensitizer chlorin e6 (Ce6) to tackle the hypoxic tumors. GMtC was capable to accumulate into the inner of murine mammary 4T1 tumor spheroids (and the depth could be as far as 90 µm) and to relieve the hypoxia state by catalytic decomposition of endogenous H2O2 to oxygen, which subsequently enhanced the yield of cytotoxic singlet oxygen under laser irradiation. In vivo dual-modal imaging of magnetic resonance and biofluorescence demonstrated the targeted accumulation and distribution of GMtC in tumor regions, thus facilitating the tumor hypoxia alleviation. Notably, GMtC achieved the highest photodynamic anticancer efficiency against 4T1 tumors without obvious systemic toxicity compared with the non-penetrating and no oxygen-generating counterparts. This study suggests the great promise of GMtC as an endogenous TME-responsive and exogenous laser-triggered theranostic platform against the solid hypoxic tumors. STATEMENT OF SIGNIFICANCE: The hostile tumor hypoxia not only induces the tumor angiogenesis, invasiveness and irreversible metastasis, but also inherently impairs the efficiency of many therapeutic modalities like photodynamic therapy (PDT). Though numerous hypoxia-alleviating strategies based on nanomedicine have been proposed, little attention is paid to the hypoxia-specific transportation barriers. This study develops a type of 2D phototheranostics GMtC against hypoxic solid tumors by integrating the function of tumor homing-penetrating and in situ oxygen-generating. GMtC displays outstanding performance in tumor deep penetration to hypoxia center and generating abundant oxygen in responsive to tumor microenvironment, thus exerting the highest efficiency of PDT against 4T1 mammary tumor. GMtC can be a potent theranostics to treat the solid hypoxic tumors.

Polydopamine-Engineered Theranostic Nanoscouts Enabling Intracellular HSP90 mRNAs Fluorescence Detection for Imaging-Guided Chemo-Photothermal Therapy.

The combination of photothermal therapy (PTT) and chemotherapy is considered a promising tumor treatment modality, nevertheless, cellular resistance induced by heat shock proteins (HSPs) overexpressed in tumor cells will restrict the therapeutic effect. Herein, a multifunctional nanobeacon DOX/HCuS@PDA-MB (D/CP-MB) with a scout function for HSP90 mRNA fluorescence detection and near-infrared (NIR) triggered drug release for sensitizing chemo-photothermal therapy, is proposed. In the theranostic nanobeacons, HSP90MBs not only enable fluorescence detection of intracellular HSP90 mRNAs, but also downregulate the expression of HSP90 to reduce cell resistance. With the assistance of NIR and guidance of fluorescence imaging, spatiotemporal doxorubicin release can be achieved by the trigger of the photothermal effect, allowing for combined chemotherapy and photothermal treatment. Furthermore, the dual photothermal effect of hollow mesoporous CuS (HCuS) and polydopamine will lead to a better photothermal effect. Moreover, compared with other control groups, D/CP-MB nanobeacons exhibit effective boost therapeutic efficacy by inducing significant suppression of tumor proliferation and enhancement of apoptosis both in vitro and in vivo. In summary, this work provides novel theranostic nanobeacons that integrate imaging and therapy in a single nanoparticle, this strategy of imaging-guided therapy can enable precise tumor treatment and effectively improve tumor treatment efficacy.

Cascade-activatable NO release based on GSH-detonated "nanobomb" for multi-pathways cancer therapy.

Therapeutic approaches of combining conventional photodynamic therapy (PDT) with other adjuvant treatments to sensitize PDT represent an appealing strategy. Herein, a novel synergetic "nanobomb" strategy based on glutathione (GSH)-responsive biodegradation was proposed to effectively destroy tumors expeditiously and accurately. This "nanobomb" was rationally constructed via the simultaneous encapsulation of methylene blue (MB) and l-arginine (L-Arg) into polyethylene glycol (PEG) modified mesoporous organosilicon nanoparticles (MON). The resulting L-Arg/MB@MP initially exhibited prolonged blood circulation, improved bioavailability, and enhanced tumor accumulation in mice after tail vein injection according to the pharmacokinetic investigations, before the nanoparticles were entirely excreted. Under laser irradiation, L-Arg/MB@MP produced remarkable reactive oxygen species (ROS) directly for PDT therapy, while a portion of ROS may oxidize L-Arg to generate nitric oxide (NO) not only for gas therapy (GT) but also serve as a biological messenger to regulate vasodilation to alleviate the tumor hypoxia. Subsequently, the rapidly released NO was further oxidized to reactive nitrogen species, which together with ROS promote immunogenic cell death by inducing G2/M cell-cycle arrest and apoptosis in cancer cells, and eventually resulting in enhanced anti-tumor immune responses. Moreover, the GSH depletion in tumor tissues induced by L-Arg/MB@MP biodegradation can cooperate with GT to amplify the therapeutic effect of PDT. These results demonstrate that this "nanobomb" provides new ideas for clinical translation to treat tumor patients in terms of synergistic PDT-GT nanotherapy in hypoxic-solid tumors.

Remodeling tumor immunosuppressive microenvironment via a novel bioactive nanovaccines potentiates the efficacy of cancer immunotherapy.

The clinical outcomes of cancer nanovaccine have been largely impeded owing to the low antigen-specific T cell response rate and acquired resistance caused by the immunosuppressive tumor microenvironment (TME). Here, we reported a tumor acidity-responsive nanovaccine to remodel the immunosuppressive TME and expand the recruitment of tumor infiltrating lymphocytes (TILs) using hybrid micelles (HM), which encapsulated colony stimulating factor 1 receptor (CSF1-R) inhibitor BLZ-945 and indoleamine 2,3-dioxygenase (IDO) inhibitor NLG-919 in its core and displayed a model antigen ovalbumin (OVA) on its surface (denoted as BN@HM-OVA). The bioactive nanovaccine is coated with a polyethylene glycol (PEG) shell for extending nanoparticle circulation. The shell can be shed in response to the weakly acidic tumor microenvironment. The decrease in size and the increase in positive charge may cause the deep tumor penetration of drugs. We demonstrated that the bioactive nanovaccine dramatically enhance antigen presentation by dendritic cells (DCs) and drugs transportation into M1-like tumor-associated macrophages (TAMs) and tumor cells via size reduction and increasing positive charge caused by the weakly acidic TME. Such bioactive nanovaccine could remodel the immunosuppressive TME into an effector T cells favorable environment, leading to tumor growth inhibition in prophylactic and therapeutic E.G7-OVA tumor models. Furthermore, combining the bioactive nanovaccine with simultaneous anti-PD-1 antibody treatment leads to a long-term tumor inhibition, based on the optimal timing and sequence of PD-1 blockade against T cell receptor. This research provides a new strategy for the development of efficient cancer immunotherapy.

Light-responsive hyaluronic acid nanomicelles co-loaded with an IDO inhibitor focus targeted photoimmunotherapy against "immune cold" cancer.

Nanomedicine enabled cancer combination immunotherapy not only sufficiently activates the host immune system, but also reprograms the immunosuppressive microenvironment, representing a new generation approach to treat cancer. Herein, we demonstrated a targeted photo- and immune-active nanoplatform termed NLG919@HA-Ce6 to simultaneously elicit efficient immunogenic cell death (ICD) using the photosensitizer Ce6 and modulate the tryptophan metabolic pathway using an indoleamine 2,3-dioxygenase (IDO) inhibitor NLG919 for the combined photodynamic therapy (PDT) and checkpoint blockade immunotherapy. Against the triple-negative and poorly immunogenic 4T1 breast cancer model, the stable spherical nanomicelle NLG919@HA-Ce6 selectively killed tumour cells via the toxic singlet oxygen upon laser excitation, thus in situ triggering a potent antitumor immune response, as seen via the obvious CRT exposure, ATP release, dendritic cell maturation, etc. Meanwhile, the IDO1-mediated immunosuppression was effectively reprogrammed to an immunostimulatory phenotype, which was accompanied by an enhanced cytotoxic T cell response as well as reduced Treg infiltration in tumour bed. Ultimately, the 4T1 tumour was synergistically suppressed by NLG919@HA-Ce6 due to the outcome of focused PDT, obvious ICD post PDT and IDO1 blockade. This study suggests the promise of NLG919@HA-Ce6 as an alternative simple, stimulative and targeted nanoagent to enable the whole-body photo-immune therapy against "immune cold" cancer.

Multistage-responsive nanovehicle to improve tumor penetration for dual-modality imaging-guided photodynamic-immunotherapy.

The exploration of an intelligent multifunctional imaging-guided therapeutic platform is of great significance because of its ideal delivery efficiency and controlled release. In this work, a tumor microenvironment (TME)-responsive nanocarrier (denoted as MB@MSP) is designed for on-demand, sequentially release of a short D-peptide antagonist of programmed cell death-ligand 1 (named as PDPPA-1) and a photosensitizer methylene blue (MB). Fe3O4-Au located in the core of MB@MSP is used as a magnetic resonance imaging and micro-computed tomography imaging contrast agent for noninvasive diagnosis of solid tumors and simultaneous monitoring of drug delivery. The PDPPA-1 coated on MB@MSP can be shed due to the cleavage of the peptide substrate by matrix metalloproteinase-2 (MMP-2) that is highly expressed in the tumor stroma, and disulfide bonding is further broken when it encounters high levels of glutathione (GSH) in TME, which finally leads to significant size reduction and charge-reversal. These transitions facilitate penetration and uptake of nanocarriers against tumors. Noticeably, the released PDPPA-1 can block the immune checkpoint to create an environment that favors the activation of cytotoxic T lymphocytes and augment the antitumor immune response elicited by photodynamic therapy, thus significantly improving therapeutic outcomes. Studies of the underlying mechanisms suggest that the designed MMP-2 and GSH-sensitive delivery system not only induce apoptosis of tumor cells but also modulate the immunosuppressive tumor microenvironment to eventually augment the suppression tumor metastasis effect of CD8+ cytotoxic T cells. Overall, the visualization of the therapeutic processes with comprehensive information renders MB@MSP an intriguing platform to realize the combined treatment of metastatic tumors.