Chimeric peptide-engineered immunostimulant for endoplasmic reticulum targeted photodynamic immunotherapy against metastatic tumor.

The combination of therapy-induced immunogenic cell death (ICD) and immune checkpoint blockade can provide a mutually reinforced strategy to reverse the poor immunogenicity and immune escape behavior of tumors. In this work, a chimeric peptide-engineered immunostimulant (ER-PPB) is fabricated for endoplasmic reticulum (ER)-targeted photodynamic immunotherapy against metastatic tumors. Among which, the amphiphilic chimeric peptide (ER-PP) is composed of ER-targeting peptide FFKDEL, hydrophilic PEG8 linker and photosensitizer protoporphyrin IX (PpIX), which could be assembled with a PD-1/PD-L1 blocker (BMS-1) to prepare ER-PPB. After passively targeting at tumor tissues, ER-PPB will selectively accumulate in the ER. Next, the localized PDT of ER-PPB will produce a lot of ROS to destroy the primary tumor cells, while increasing the ER stress to initiate a robust ICD cascade. Moreover, the concomitant delivery of BMS-1 can impede the immune escape of tumor cells through PD-1/PD-L1 blockade, thus synergistically activating the immune system to combat metastatic tumors. In vitro and in vivo results demonstrate the robust immune activation and metastatic tumor inhibition characteristics of ER-PPB, which may offer a promising strategy for spatiotemporally controlled metastatic tumor therapy.

Nurse-led World Café approach in promoting interprofessional collaborative behaviors and learning engagement among healthcare professionals.

Effective interprofessional collaboration practice (IPCP) promotes healthcare outcomes but is often hindered by poor communication. Traditional teaching methods with limited interdisciplinary interactions may not effectively foster IPCP behaviors. This study evaluated the effectiveness of nurse-led World Cafe (NWC) approach in promoting IPCP behaviors and learning engagement. Seventy-six healthcare professionals (38 in each group) participated in this quasi-experimental study. Data were collected before, one-week, and four-week post-intervention, using Lee's (2016) Interprofessional Collaborative Practice Behavior Inventory (IPCPBI) and Ciou's (2020) Learning Engagement Scale. Five medical technologists in the control group were excluded from data analysis to ensure group equivalence. Before the intervention, there were no significant differences in IPCPBI between groups. One week post-intervention, the experimental group scored higher in IPCPBI, yet lacked statistical significance (p > .05). Four weeks post-intervention, the experimental group significantly improved in IPCPBI (p < .05). While no statistically significance was found in learning engagement between groups, the experimental group scored significantly higher in the active engagement sub-domain (p < .05). The NWC approach boosted IPCP behaviors and learning engagement, fostering a collaborative learning environment that improves outcomes through interdisciplinary interactions. Healthcare settings could benefit from adopting the NWC approach to enhance clinicians' IPCP competency.

Cpne1 deficiency preserves sperm motility under Ca2+ channel blockade.

Calcium ions (Ca2+) play crucial roles in sperm motility and fertilization. The copine (CPNE) family comprises several Ca2+-dependent phospholipid-binding proteins. Of these, CPNE1 is extensively expressed in mammalian tissues; however, its precise role in testicular development and spermatogenesis is yet to be fully characterized. In this study, we used proteomics to analyze testicular biopsies and found that levels of CPNE1 were significantly reduced in patients with non-obstructive azoospermia (defective spermatogenesis) compared to those in patients with obstructive azoospermia (physiological spermatogenesis). In mice, CPNE1 is expressed at various stages of germ cell development and is associated with the Golgi apparatus. Ultimately, CPNE1 is expressed in the flagella of mature sperms. To further examine the role of CPNE1, we developed a Cpne1 knockout mouse model. Analysis showed that the loss of Cpne1 did not impair testicular development, spermatogenesis, or sperm morphology and motility in physiological conditions. When treated with gadolinium (III) chloride or 2-aminoethoxydiphenyl borate, known inhibitors of store-operated Ca2+ entry, Ca2+ signals and sperm motility were significantly compromised in wild-type mice; however, both mechanisms were conserved in KO mice. These results suggested that CPNE1 is dispensable for testicular development, spermatogenesis or sperm motility in physiological conditions. In addition, CPNE1 may represent a target of Ca2+ channel inhibitors and may therefore be implicated in the regulation of Ca2+ signaling and sperm motility.

Chlorin e6 and BLZ945 Based Self-Assembly for Photodynamic Immunotherapy Through Immunogenic Tumor Induction and Tumor-Associated Macrophage Depletion.

Immunotherapeutic effect is restricted by the nonimmunogenic tumor phenotype and immunosuppression behaviors of tumor-associated macrophages (TAMs). In this work, a drug self-assembly (designated as CeBLZ) is fabricated based on chlorin e6 (Ce6) and BLZ945 to activate photodynamic immunotherapy through tumor immunogenic induction and tumor-associated macrophage depletion. It is found that Ce6 tends to assemble with BLZ945 without any drug excipients, which can enhance the cellular uptake, tumor penetration, and blood circulation behaviors. The robust photodynamic therapy effect of CeBLZ efficiently suppresses the primary tumor growth and also triggers immunogenic cell death to reverse the nonimmunogenic tumor phenotype. Moreover, CeBLZ can deplete TAMs in tumor tissues to reverse the immunosuppression microenvironment, activating abscopal effect for distant tumor inhibition. In vitro and in vivo results confirm the superior antitumor effect of CeBLZ with negligible side effect, which might promote the development of sophisticated drug combinations for systematic tumor management.

[Excelling in the AI Era: Cultivating AI Literacy].

In light of the rapid advancements in artificial intelligence (AI), the future of the nursing profession is expected to be closely intertwined with AI applications. In response to this challenge, nursing educators must cultivate AI literacy in students to ensure their ability to communicate and collaborate effectively with their interdisciplinary peers. Nursing educators should comprehend the essence of AI literacy, integrate AI literacy into their curriculum designs, and regularly assess the effectiveness of AI literacy cultivation efforts among their students to ensure nursing graduates are able to effectively fulfill their roles in nursing and healthcare. The purpose of this paper is to explain the essence of AI literacy, approaches for cultivating AI literacy in students, and methods for assessing AI literacy with the aim of educating nursing students to become competent nurses for tomorrow.

Standardized patients' experiences of portraying characters in difficult communication scenarios: Narrative inquiry.

BACKGROUND: There are limited studies that explored the preparation and challenges faced by standardized patients (SPs) in portraying characters in difficult communication scenarios, and the strategies used to overcome these challenges. The purpose of this study was to understand the experience of SPs in interpreting difficult communication situations and the learning needs of performing similar scenarios. And it allows the researchers to explore the meaning, beliefs, values, and aspiration associated with their role as SPs. The findings could shade light on the significance of their experiences and provide valuable insights for the development of future SP training programs. METHODS: The design of this study is framed by a narrative inquiry, using semi-structured guidelines to conduct in-depth interviews with 11 SPs who have participated in the performances of difficult communication situations. Research data were analyzed by Polkinghorne narrative analysis, and Riessman's four criteria were used to establish rigor. RESULTS: Analysis revealed the following five themes: scenarios to real life connections, process of preparing for a performance, methods to detach from character, obtaining unexpected rewards, and needs for performance training. There are two to three subthemes that are subsumed under each theme. CONCLUSIONS: To strengthen training in difficult communication for healthcare professionals, the use of SPs to interpret challenging difficult communication scenarios will continue to increase. Educators need to ensure that SPs are fully prepared physically and emotionally before, during and after their performance. Offering of continuing education and training in feedback techniques are crucial to extend the tenure of SPs, reduce their frustration, prevent attrition, and ultimately, reduce training costs. In the future, SP training should also include detachment and feedback techniques to alleviate SPs' stress.

Chemotherapy-Enabled Colorectal Cancer Immunotherapy of Self-Delivery Nano-PROTACs by Inhibiting Tumor Glycolysis and Avoiding Adaptive Immune Resistance.

The chemo-regulation abilities of chemotherapeutic medications are appealing to address the low immunogenicity, immunosuppressive lactate microenvironment, and adaptive immune resistance of colorectal cancer. In this work, the proteolysis targeting chimera (PROTAC) of BRD4 (dBET57) is found to downregulate colorectal cancer glycolysis through the transcription inhibition of c-Myc, which also inhibits the expression of programmed death ligand 1 (PD-L1) to reverse immune evasion and avoid adaptive immune resistance. Based on this, self-delivery nano-PROTACs (designated as DdLD NPs) are further fabricated by the self-assembly of doxorubicin (DOX) and dBET57 with the assistance of DSPE-PEG2000. DdLD NPs can improve the stability, intracellular delivery, and tumor targeting accumulation of DOX and dBET57. Meanwhile, the chemotherapeutic effect of DdLD NPs can efficiently destroy colorectal cancer cells to trigger a robust immunogenic cell death (ICD). More importantly, the chemo-regulation effects of DdLD NPs can inhibit colorectal cancer glycolysis to reduce the lactate production, and downregulate the PD-L1 expression through BRD4 degradation. Taking advantages of the chemotherapy and chemo-regulation ability, DdLD NPs systemically activated the antitumor immunity to suppress the primary and metastatic colorectal cancer progression without inducing any systemic side effects. Such self-delivery nano-PROTACs may provide a new insight for chemotherapy-enabled tumor immunotherapy.

Using "board games" to improve the effectiveness of extracorporeal membrane oxygenation care for nurses in intensive care unit.

AIM: The purpose of this study was to evaluate the effectiveness of ECMO care board games facilitated teaching approach (ECMO care board games) in enhancing ECMO care knowledge, clinical reasoning and learning engagement among intensive care unit (ICU) nurses. BACKGROUND: ECMO is a highly complex, relatively low-incidence, high-risk clinical life support device system used in the intensive care unit (ICU). Its usage has increased nearly tenfold over the past 30 years. Traditionally, ECMO education has been delivered through classroom teaching, which has demonstrated limited effectiveness in promoting nurses' learning engagement, clinical reasoning competency and confidence. The literature suggests that well-designed board games can enhance learning engagement, stimulate higher-level thinking and improve the effectiveness and confidence of nurses' learning. DESIGN: A quasi-experimental study two-group repeated measure design. METHODS: A purposive sample of 73 ICU nurses from two campuses of one medical center was recruited (37 in the experimental group and 36 in the control group). The experimental group received ECMO care training through ECMO care board games facilitated teaching approach, whereas the control group completed the training through a traditional teaching approach. Instruments used for data collection include a demographic information sheet, ECMO Care Knowledge Scale, Clinical Reasoning Scale (Huang et al., 2023) and Learning Engagement Scale (Ciou , 2020). Both groups completed a pre-test before the training, a post-test one week after the training and a second post-test three weeks after the training. RESULTS: Prior to the intervention, there were no significant differences between the two groups in ECMO care knowledge and learning engagement. However, there was a significant difference in clinical reasoning. One week after the intervention, the experimental group demonstrated significantly higher scores in ECMO care knowledge, clinical reasoning and learning engagement than the control group (p <0.01). Three weeks after the intervention, the experimental group showed significantly higher scores in ECMO care knowledge, clinical reasoning and learning engagement (p <0.001). CONCLUSIONS: The content for ECMO care is complex and difficult. Board games can enhance ECMO care knowledge, clinical reasoning and learning engagement. This teaching strategy may be applied to learning challenging subjects in the future to improve learning effectiveness. The clinical reasoning framework is conducive to guiding nurses' learning. In future continuing education, board games designed based on the clinical reasoning framework and tailored to the focus of in-service education can effectively enhance nurses' learning effectiveness.

Application of the Ohio Nurse Competency Model in a BSN Leadership/Management Course.

ABSTRACT: Strategically preparing students to meet practice expectations is a priority for nursing educators. The Ohio Nurse Competency Model (ONCM) was applied as the organizing framework for a senior baccalaureate leadership/management course. The purpose of this pretest/posttest descriptive study was to evaluate changes in students' confidence in understanding, applying, and valuing the ONCM. Paired t -tests found statistically significant increases in confidence levels for all ONCM competencies among 56 students with greatest increases in systems-based practice and informatics and technology. Nurse educators are encouraged to intentionally structure and organize course content and curricula according to state and national competency models/guidelines.

Chimeric Peptide-Engineered Self-Delivery Nanomedicine for Photodynamic-Triggered Breast Cancer Immunotherapy by Macrophage Polarization.

A systemic treatment strategy is urgently demanded to suppress the rapid growth and easy metastasis characteristics of breast cancer. In this work, a chimeric peptide-engineered self-delivery nanomedicine (designated as ChiP-CeR) for photodynamic-triggered breast cancer immunotherapy by macrophage polarization. Among these, ChiP-CeR is composed of the photosensitizer of chlorine e6 (Ce6) and the TLR7/8 agonist of lmiquimod (R837), which is further modified with tumor matrix targeting peptide (Fmoc-K(Fmoc)-PEG8 -CREKA. ChiP-CeR is preferred to actively accumulate at the tumor site via specific recognition of fibronectin, which can eradicate primary tumor growth through photodynamic therapy (PDT). Meanwhile, the destruction of primary tumors would trigger immunogenic cell death (ICD) effects to release high-mobility group box-1(HMGB1) and expose calreticulin (CRT). Moreover, ChiP-CeR can also polarize M2-type tumor-associated macrophages (TAMs) into M1-type TAMs, which can activate T cell antitumor immunity in combination with ICD. Overall, ChiP-CeR possesses superior antitumor effects against primary and lung metastatic tumors, which provide an applicable nanomedicine and a feasible strategy for the systemic management of metastatic breast cancer.

[Development and Validation of the Outpatient Nurses Communication Behavior Inventory].

BACKGROUND: Outpatient clinics in medical centers are the most common location where people seek medical treatment. Because they must provide patients with treatment information in a timely manner, good communication skills are a key competency for outpatient nurses. However, the tools available for communication behavior assessment are general and rarely tailored for outpatient settings. PURPOSE: The purpose was to develop a communication behavior inventory for outpatient nurses and to examine its reliability and validity. METHODS: During phase one, the authors conducted a literature search and synthesis, using the findings to develop the Outpatient Nurses Communication Behavior Inventory. During phase two, two expert validation rounds were conducted to confirm content validity. During phase three, 220 licensed outpatient nurses were recruited from a medical center in northern Taiwan to complete the instrument (December 2018 - January 2019.) The construct validity and internal consistency of the inventory were evaluated. RESULTS: The literature search and synthesis identified six domains of communication, including connect, introduce, communicate, ask, respond, and exit. A total of 25 items were generated. Following the two expert panel validation rounds, the six domains remained but the inventory items were reduced to 21. Both item-content validity index and scale-level content validity index were 1.0. In phase three, the results of the confirmatory factor analysis retained six factors with a total of 16 items. Model three showed that the inventory demonstrated goodness of fit (Χ ² = 155.75, p < .001, RMSEA = .06, GFI = .92, AGFI = .87, NNFI = .97, NFI = .95, Model AIC = 253.75). Internal consistency was demonstrated with a Cronbach's α of .89. CONCLUSIONS / IMPLICATIONS FOR PRACTICE: The Outpatient Nurses Communication Behavior Inventory exhibits good reliability and validity and may be used to assess outpatient nurses' communication behaviors and as a basis for education. The six CICARE (connect, introduce, communicate, ask, respond and exit) domains may be utilized to remind outpatient nurses to demonstrate effective communication consistently, promote outpatient nurses' communication with patients, and improve quality of care.

The efficacy of acupuncture for attention deficit hyperactivity disorder (ADHD): An overview of systematic reviews and meta-analyses.

BACKGROUND: Attention deficit hyperactivity disorder (ADHD) is one of the most common neurological and mental developmental disorders in children. Published systematic reviews (SRs) and meta-analyses (MAs) concerning the use of acupuncture for ADHD have compared the efficacy of acupuncture treatment to that of drug therapies. However, the quality of these articles has not been evaluated and the evidence varies widely. OBJECTIVE: To summarize and assess the efficacy of acupuncture for ADHD based on existing SRs and MAs. METHODS: A systematic search of the literature was conducted from inception until September 16 2021, using seven electronic databases. The AMSTAR-2 tool was used to evaluate the quality of SRs and MAs, and the GRADE system was used to assess the quality of evidence. RESULTS: There are a total of five SRs and MAs included in this overview. Using the AMSTAR-2, three articles were rated as having 'Low' quality, while two were rated as having of 'Critically Low' quality. The GRADE system was used to measure the quality of evidence for ten outcomes (five response rate outcomes, three Conners' Index of Hyperactivity (CIH) score outcomes, one Conners' rating scale score outcome, and one Chinese medicine syndrome outcome) across the five included MAs. Four of the ten outcomes demonstrated 'moderate' quality, four demonstrated 'low' quality, and two demonstrated 'very low' quality. The risk of bias and inconsistency accounted for most downgrading factors in the included reviews. CONCLUSION: It is still debatable whether acupuncture is efficacious in improving the CIH score and the Response rate. Considering the heterogeneity of clinical trials and the fact that this study did not search and evaluate the relevant data of each randomized controlled trial, large-sample and high-quality randomized controlled trials are still needed to draw reliable conclusions regarding acupuncture's role in treating ADHD. Due to the poor quality of existing available evidence, little inference can be drawn from the included studies.

Carrier-Free Nano-PROTACs to Amplify Photodynamic Therapy Induced DNA Damage through BRD4 Degradation.

Therapy-induced DNA damage is the most common strategy to inhibit tumor cell proliferation, but the therapeutic efficacy is limited by DNA repair machinery. Carrier-free nanoproteolysis targeting chimeras (PROTACs), designed as SDNpros, have been developed to enhance photodynamic therapy (PDT) by blocking the DNA damage repair pathway through BRD4 degradation. Specifically, SDNpros are constructed through noncovalent interactions between the photosensitizer of chlorine e6 (Ce6) and PROTACs of BRD4 degrader (dBET57) via self-assembly. SDNpro has favorable dispersibility and a uniform nanosize distribution without drug excipients. Upon light irradiation, SDNpro produces abundant reactive oxygen species (ROS) to induce DNA oxidative damage. Meanwhile, the DNA repair pathway would be interrupted by the concurrent degradation of BRD4, which could intensify the oxidative DNA damage and elevate PDT efficiency. Beneficially, SDNpro suppresses tumor growth and avoids systemic side effects, providing a promising strategy to promote the clinical translation of PROTACs for tumor treatment.

Using AGREE II reporting checklist to evaluate the quality of Tuina clinical practice guidelines.

Objective: The objective of this study is to evaluate the methodological quality of Tuina clinical practice guidelines (CPGs). Methods: Computer searches of China National Knowledge Infrastructure (CNKI), Chinese Technical Periodicals (VIP), Wanfang Data Knowledge Service Platform, PubMed, Cochrane Library, Embase, and other databases were conducted to search for published guidelines on Tuina, with a search time frame from database creation to March 2021. Four evaluators independently used the Appraisal of Guidelines for Research and Evaluation II instrument to evaluate the quality of the included guidelines. Results: A total of eight guidelines related to Tuina were included in this study. The quality of reporting was low in all included guidelines. The highest quality report had a total score of 404 and was rated as "highly recommended." The worst guideline had a final score of 241 and was rated as "not recommended." Overall, 25% of the included guidelines were recommended for clinical use, 37.5% were recommended after revision, and 37.5% were not recommended. Conclusion: The number of existing Tuina clinical practice guidelines is limited. The methodological quality is low, far from the internationally accepted clinical practice guideline development and reporting norms. In the future, reporting specifications of guidelines and the methodology of guideline development, including the rigor of the guideline development process, the clarity, application, and independence of reporting, should be emphasized in the development of the Tuina guidelines. These initiatives could improve the quality and applicability of clinical practice guidelines to guide and standardize the clinical practice of Tuina.

Paraptosis Inducer to Effectively Trigger Immunogenic Cell Death for Metastatic Tumor Immunotherapy with IDO Inhibition.

Paraptosis is characterized by the extensive vacuolization of endoplasmic reticulum (ER) and mitochondria, which will cause the release of damage-associated molecular patterns to promote immunogenic cell death (ICD). However, the tumor can develop an immunosuppressive microenvironment to affect the ICD activation for the purpose of immune escape. Herein, a paraptosis inducer (CMN) is constructed to amplify the ICD effect for efficient immunotherapy by inhibiting the activity of indoleamine 2,3-dioxygenase (IDO). Initially, CMN is prepared by the assembly of copper ions (Cu2+), morusin (MR), and IDO inhibitor (NLG919) through noncovalent interactions. Without the need for extra drug carriers, CMN possesses very high drug contents and exhibits a favorable GSH responsiveness for disassembly. Subsequently, the released MR can trigger paraptosis to cause extensive vacuolization of ER and mitochondria, contributing to activating ICD for immunotherapy. Moreover, NLG919 would inhibit IDO to remodel the tumor microenvironment and promote the activation of cytotoxic T cells, leading to an intensive antitumor immunity. Abundant in vivo studies indicate that CMN is superior in suppressing the proliferations of not only primary tumor but also metastatic and rechallenged tumors. Such a GSH-responsive paraptosis inducer might provide a promising strategy to trigger ICD and enhance tumor immunotherapy.

Targeting glutamine metabolism with photodynamic immunotherapy for metastatic tumor eradication.

Immune checkpoint blockade (ICB) has shown significant clinical success, yet its responses can vary due to immunosuppressive tumor microenvironments. To enhance antitumor immunity, combining ICB therapy with tumor metabolism reprogramming may be a promising strategy. In this study, we developed a photodynamic immunostimulant called BVC aiming to boost immune recognition and prevent immune escape for metastatic tumor eradication by reprogramming glutamine metabolism. BVC, a carrier free self-assembled nanoparticle, comprises a photosensitizer (chlorin e6), an ASCT2 inhibitor (V9302) and a PD1/PDL1 blocker (BMS-1), offering favorable stability and enhanced drug delivery efficiency. The potent photodynamic therapy (PDT) capability of BVC is attributed to its regulation of glutamine metabolism, which influences the redox microenvironment within tumor tissues. By targeting ASCT2-mediated glutamine metabolism, BVC inhibits glutamine transport and GSH synthesis, leading to the upregulation of Fas and PDL1. Additionally, BVC-mediated PDT induces immunogenic cell death, triggering a cascade of immune responses. Consequently, BVC not only enhances immune recognition between CD8+ T cells and Fas-overexpressing tumor cells but also reduces tumor cell immune escape through PD1/PDL1 blockade, significantly benefiting metastatic tumor eradication. This study paves a novel approach for multi-synergistic tumor treatment.

Development and Psychometric Testing of the Clinical Reasoning Scale Among Nursing Students Enrolled in Three Types of Programs in Taiwan.

BACKGROUND: There is no instrument currently available to assess the essential nursing competency of clinical reasoning (CR). PURPOSE: The purpose of this study was to develop and test the psychometric properties of CR assessment instrument appropriate for use with nursing students across different types of programs. METHODS: H. M. Huang et al.'s (2018) Framework of Competencies of Clinical Reasoning for Nursing Students was used to guide this study. Two rounds of Delphi study and confirmatory factor analysis (CFA) were conducted to test content and construct validity. Internal consistency was tested for reliability. RESULTS: The four-domain, 16-item Likert-scale Clinical Reasoning Scale (CRS) was developed. One thousand five hundred four nursing students currently enrolled in three different types of nursing programs completed the CRS. The content validity index was .85-1.0, the CFA indicated goodness of fit, and the Cronbach's α score range was .78-.89. CONCLUSION: The CRS is a valid and reliable tool for assessing CR in nursing students in different types of nursing program.

Self-delivery biomedicine for enhanced photodynamic therapy by feedback promotion of tumor autophagy.

Reactive oxygen species (ROS) generated during photodynamic therapy (PDT) can induce autophagy to protect tumor cell from PDT-induced apoptosis. In this work, a self-delivery autophagy regulator (designated as CeCe) is developed for autophagy promotion sensitized PDT against tumor. Briefly, CeCe is prepared by the assembly of a photosensitizer of chlorin e6 (Ce6) and autophagy promoter of celastrol. By virtue of intermolecular interactions, Ce6 and celastrol are able to self-assemble into nanomedicine with great photodynamic performance and autophagy regulation capacity. Under light irradiation, CeCe would produce ROS in tumor cells to amplify the oxidative stress and promote cell autophagy. As a result, CeCe exhibits an enhanced photo toxicity by inducing autophagic cell death. In vivo experiments indicate that CeCe can predominantly accumulate in tumor tissue for a robust PDT. Moreover, CeCe has a superior therapeutic efficiency compared to monotherapy and combined treatment of Ce6 and celastrol, suggesting a synergistic antitumor effect of PDT and autophagy promotion. This self-delivery nanomedicine may advance the development of the co-delivery nanoplatform to improve the antitumor efficacy of PDT by promoting autophagy. STATEMENT OF SIGNIFICANCE: Autophagy is a "double-edged sword" in cellular homeostasis and metabolism, which can promote tumor progression but also induce an unknown impact on tumor inhibition. In this work, a self-delivery autophagy regulator (designated as CeCe) was developed for autophagy promotion sensitized photodynamic therapy (PDT). By virtue of intermolecular interactions, Ce6 and celastrol were found to self-assemble into stable CeCe without drug excipients, which exhibited great photodynamic performance and autophagy regulation capacity. In vitro and in vivo findings demonstrated a superior tumor suppression ability of CeCe over the monotherapy as well as the combined treatment of Ce6 and celastrol, suggesting a synergistic antitumor efficacy by PDT and autophagy promotion.

Cascade Immune Activation of Self-Delivery Biomedicine for Photodynamic Immunotherapy Against Metastatic Tumor.

Photodynamic therapy (PDT) can generate reactive oxygen species (ROS) to cause cell apoptosis and induce immunogenic cell death (ICD) to activate immune response, becoming a promising antitumor modality. However, the overexpressions of indoleamine 2,3-dioxygenase (IDO) and programmed cell death ligand 1 (PD-L1) on tumor cells would reduce cytotoxic T cells infiltration and inhibit the immune activation. In this paper, a simple but effective nanosystem is developed to solve these issues for enhanced photodynamic immunotherapy. Specifically, it has been constructed a self-delivery biomedicine (CeNB) based on photosensitizer chlorine e6 (Ce6), IDO inhibitor (NLG919), and PD1/PDL1 blocker (BMS-1) without the need for extra excipients. Of note, CeNB possesses fairly high drug content (nearly 100%), favorable stability, and uniform morphology. More importantly, CeNB-mediated IDO inhibition and PD1/PDL1 blockade greatly improve the immunosuppressive tumor microenvironments to promote immune activation. The PDT of CeNB not only inhibits tumor proliferation but also induces ICD response to activate immunological cascade. Ultimately, self-delivery CeNB tremendously suppresses the tumor growth and metastasis while leads to a minimized side effect. Such simple and effective antitumor strategy overcomes the therapeutic resistance against PDT-initiated immunotherapy, suggesting a potential for metastatic tumor treatment in clinic.

Epigenetic reprogramming of carrier free photodynamic modulator to activate tumor immunotherapy by EZH2 inhibition.

Tumor cells are characterized by unlimited proliferation and escape of immune clearance, which are closely associated with the down regulation of surface antigens. In this work, a carrier free photodynamic modulator (CeTaz) is developed to improve immunosuppressive tumor microenvironment and promote the recognition of tumors by T cells by epigenetic reprogramming. Specifically, CeTaz is assembled by chlorine e6 (Ce6) and tazemetostat (Taz) through intermolecular interactions. Upon light irradiation, CeTaz is able to promote the generation of reactive oxygen species (ROS) for a robust photodynamic therapy (PDT) to inhibit localized tumor growth. Meanwhile, the PDT also induces immunogenic cell death (ICD) to initiate immune response, leading to the activation of effector T cells. More importantly, CeTaz could inhibit the epigenetic regulator of EZH2 to suppress the methylation of H3K27, which would promote tumor cells to express MHC-I and release CXCL10. Consequently, the epigenetically reprogrammed tumor cells are readily recognized by effector T cells to enhance the antitumor immunity. Results indicate that the PDT activated immunotherapy of CeTaz could simultaneously inhibit the growth of primary and distant tumors with a low system toxicity. This study would advance the development of carrier free nanomedicine for precise treatment of metastatic tumor.