Membrane Fusion Liposomes Deliver Antifibrotic and Chemotherapeutic Drugs Sequentially to Enhance Tumor Treatment Efficacy by Reshaping Tumor Microenvironment.

The intricate tumor microenvironment in triple-negative breast cancer (TNBC) hampers chemotherapy and immunotherapy efficacy due to dense extracellular matrix (ECM) by tumor-associated fibroblasts (TAFs). Nanoparticle-based therapies, especially "all-in-one" nanoparticles, have shown great potential in combined drug delivery strategies to reshape the tumor microenvironment and enhance therapeutic efficiency. However, these "all-in-one" nanoparticles suffer from limitations in targeting different target cells, uncontrollable dosing ratio, and disregarding the impact of delivery schedules. This study prepared cell membrane fusion liposomes (TAFsomes and CCMsomes) to load FDA-approved antifibrotic drug pirfenidone (PFD/TAFsomes) and antitumor drug doxorubicin (DOX/CCMsomes). These liposomes can specifically target TAFs cells and tumor cells, and combined administration can effectively inhibit TAFs activity, reshape the tumor microenvironment (TME), and significantly enhance the tumor chemotherapy efficacy. Combined drug delivery defeats "all-in-one" liposomes (DOX/PFD/Liposomes, DOX/PFD/TAFsomes, and DOX/PFD/CCMsomes) by flexibly adjusting the drug delivery ratio. Moreover, an asynchronous delivery strategy that optimizes the administration schedule not only further improves the therapeutic effect, but also amplifies the effectiveness of α-PD-L1 immunotherapy by modulating the tumor immune microenvironment. This delivery strategy provides a personalized treatment approach with clinical translation potential, providing new ideas for enhancing the therapeutic effect against solid tumors such as TNBC.

Association Between Composite Dietary Antioxidant Index and the Risk of Endometriosis-Related Rheumatoid Arthritis in Women of Childbearing Age: A Cross-Sectional Study Based on the National Health and Nutrition Examination Survey Database.

Purpose: To evaluate the association between Composite Dietary Antioxidant Index (CDAI) and the risk of endometriosis (EM)-related rheumatoid arthritis (RA) in women of childbearing age. Methods: Using the data from the National Health and Nutrition Examination Survey database, this cross-sectional study included women of childbearing age. The CDAI was obtained by summing the standardized Z-values of the dietary intakes. EM was diagnosed based on a questionnaire-based survey. The outcome of this study was the presence of RA, which was defined by a questionnaire. The associations of CDAI and EM with the risk of RA were determined using weighted logistic analysis. Additive interaction was evaluated using the relative excess risk due to interaction (RERI), the attributable proportion due to interaction (AP), and the synergy index (S). Results: In total, 3803 patients were included, of which 74 patients (1.99%) were with RA. A lower CDAI [odds ratio (OR): 1.85, 95% confidence interval (CI): 1.12 to 3.04, P= 0.015] and the presence of EM (OR: 3.05, 95% CI: 1.19 to 7.81, P= 0.023) was associated with the risk of RA. The result demonstrated an additive interaction of a lower CDAI and the presence of EM on the risk of RA (OR: 6.19, 95% CI: 2.33 to 16.43, P <0.001, P of trend =0.007). Nevertheless, there was no significant additive interaction after being assessed by the RERI, AP, and S. However, a joint effect of a lower CDAI and EM on the risk of RA (OR: 3.94, 95% CI: 1.35 to 11.51, P= 0.013) was observed. Conclusion: Our study identified EM, and lower CDAI, was related to the risk of RA. Lower CDAI score was also associated with the risk of EM-related RA. This study indicates the importance of antioxidant intake in daily diet for the management of EM-related RA.

Inhibitory effects and reactions of gallic acid, catechin, and procyanidin B2 with nitrosation under stomach simulating conditions.

Nitrite widely exists in meat products, and has the functions of bacteriostasis, antisepsis, and color development. However, in an acidic environment, nitrite will react with amines, and further generate nitrosamines with carcinogenic and teratogenic effects. Polyphenols have good antioxidant and nitrite-scavenging effects. This study aimed to evaluate the inhibitory effects of gallic acid, catechin, and procyanidin B2 on the nitrosation reaction under stomach simulating conditions and discuss the potential inhibitory mechanism. The nitrite scavenging rate and nitrosamine synthesis blocking rate of gallic acid, catechin, and procyanidin B2 under different reaction times and contents was determined by UV-vis spectrophotometry. The possible products of the reaction of the three polyphenols with nitrite were analyzed by high-performance liquid chromatography-mass spectrometry (HPLC-MS) to reveal the mechanism of inhibiting nitrification. The results showed that the scavenging rate of the three polyphenols on nitrite and the blocking rate of nitrosamine synthesis increased with the increase of the content and reaction time. The ability of the three polyphenols to inhibit nitrosation was catechin > procyanidin B2 > gallic acid. HPLC-MS analysis showed that under simulated gastric juice conditions, the three phenolics were oxidized by nitrous acid to form their semiquinone radicals as the intermediates and nitrosated derivatives, while nitrite might be converted to ˙NO. These results suggested that gallic acid, catechin, and procyanidin B2 could inhibit nitrosation reactions in an acidic environment and may be used as food additives to reduce nitrite residues and nitrosamines in food.

Unlocking the power of immunotherapy: Combinatorial delivery of plasmid IL-15 and gemcitabine to synergistically remodeling the tumor microenvironment.

Cancer immunotherapy has emerged as a promising clinical treatment strategy in recent years. Unfortunately, the satisfactory antitumor therapeutic efficacy of immunotherapy is limited by intricate immunosuppressive tumor microenvironment (ITM). To remodel the ITM and alleviate the immune evasion, we constructed FA-PEG-modified liposomes to deliver plasmid IL-15 (pIL-15) and gemcitabine (GEM) (FPCL@pIL-15 + FPGL), respectively. The FPCL@pIL-15 (150 nm) and FPGL (120 nm) exhibited symmetrically spherical structures as well as desirable penetration and accumulation on tumor tissue depending on folic acid (FA) specialized targeting function. The transfected expression of IL-15 efficiently fosters the proliferation and co-activation of Natural killer (NK) cells and CD8+T cells through binding to IL-15R. FPGL upregulated the expression of Natural killer group 2 member D ligands (NKG2DLs) and reinforced recognition by NK cells to alleviate the immune evasion, and simultaneously promoted activation of CD8+T cells through immunogenic cell death (ICD) effects. More importantly, the combinatorial administration achieved intended anti-tumor efficacy in the subcutaneous 4T1 tumor model. In essence, we demonstrated that combining FPCL@pIL-15 with FPGL synergistically stimulates and mobilizes the immune system to reverse the ITM and trigger an anti-tumor immune response, indicating a tremendous potential for application in immunotherapy.

Tumor-Educated Platelet RNA and Circulating Free RNA: Emerging Liquid Biopsy Markers for Different Tumor Types.

The incidence and mortality from malignant tumors continue to rise each year. Consequently, early diagnosis and intervention are vital for improving patient' prognosis and survival. The traditional pathological tissue biopsy is currently considered the gold standard for cancer diagnosis. However, it suffers from several limitations including invasiveness, sometimes not repeatable or unsuitable, and the inability to capture the dynamic nature of tumors in terms of space and time. Consequently, these limit the application of tissue biopsies for the diagnosis of early-stage tumors and have redirected the research focus towards liquid biopsies. Blood-based liquid biopsies have thus emerged as a promising option for non-invasive assessment of tumor-specific biomarkers. These minimally invasive, easily accessible, and reproducible tests offer several advantages, such as being mostly complication-free and efficient at monitoring tumor progression and tracing drug resistance. Liquid biopsies show great potential for cancer prediction, diagnosis, and prognostic assessment. Circulating tumor-educated platelets (TEPs) possess the unique ability to absorb nucleic acids from the bloodstream and to modify transcripts derived from megakaryocytes in response to external signals. In addition, circulating free RNA (cfRNA) constitutes a significant portion of the biomolecules present in the bloodstream. This paper aims to provide a comprehensive overview of the current research status regarding TEP RNA and cfRNA in liquid biopsies from various tumor types. Our analysis includes cancers of the lung, liver, pancreas, breast, nasopharynx, ovary and colon, as well as multiple myeloma and sarcoma. By synthesizing this information, we intend to establish a solid theoretical foundation for exploring potential applications of circulating RNA as a reliable biomarker for tumor diagnosis and monitoring.

CSNK1A1/CK1α suppresses autoimmunity by restraining the CGAS-STING1 signaling.

STING1 (stimulator of interferon response cGAMP interactor 1) is the quintessential protein in the CGAS-STING1 signaling pathway, crucial for the induction of type I IFN (interferon) production and eliciting innate immunity. Nevertheless, the overactivation or sustained activation of STING1 has been closely associated with the onset of autoimmune disorders. Notably, the majority of these disorders manifest as an upregulated expression of type I interferons and IFN-stimulated genes (ISGs). Hence, strict regulation of STING1 activity is paramount to preserve immune homeostasis. Here, we reported that CSNK1A1/CK1α, a serine/threonine protein kinase, was essential to prevent the overactivation of STING1-mediated type I IFN signaling through autophagic degradation of STING1. Mechanistically, CSNK1A1 interacted with STING1 upon the CGAS-STING1 pathway activation and promoted STING1 autophagic degradation by enhancing the phosphorylation of SQSTM1/p62 at serine 351 (serine 349 in human), which was critical for SQSTM1-mediated STING1 autophagic degradation. Consistently, SSTC3, a selective CSNK1A1 agonist, significantly attenuated the response of the CGAS-STING1 signaling by promoting STING1 autophagic degradation. Importantly, pharmacological activation of CSNK1A1 using SSTC3 markedly repressed the systemic autoinflammatory responses in the trex1-/- mouse autoimmune disease model and effectively suppressed the production of IFNs and ISGs in the PBMCs of SLE patients. Taken together, our study reveals a novel regulatory role of CSNK1A1 in the autophagic degradation of STING1 to maintain immune homeostasis. Manipulating CSNK1A1 through SSTC3 might be a potential therapeutic strategy for alleviating STING1-mediated aberrant type I IFNs in autoimmune diseases.Abbreviations: BMDMs: bone marrow-derived macrophages; cGAMP: cyclic GMP-AMP; CGAS: cyclic GMP-AMP synthase; HTDNA: herring testes DNA; IFIT1: interferon induced protein with tetratricopeptide repeats 1; IFNA4: interferon alpha 4; IFNB: interferon beta; IRF3: interferon regulatory factor 3; ISD: interferon stimulatory DNA; ISGs: IFN-stimulated genes; MEFs: mouse embryonic fibroblasts; PBMCs: peripheral blood mononuclear cells; RSAD2: radical S-adenosyl methionine domain containing 2; SLE: systemic lupus erythematosus; STING1: stimulator of interferon response cGAMP interactor 1; TBK1: TANK binding kinase 1.

STING signaling in islet macrophages impairs insulin secretion in obesity.

The innate immune regulator stimulator of interferon genes (STING) mediates self-DNA sensing and leads to the induction of type I interferons and inflammatory cytokines, which promotes the progression of various inflammatory and autoimmune diseases. Innate immune system plays a critical role in regulating obesity-induced islet dysfunction, whereas the potential effect of STING signaling is not fully understood. Here, we demonstrate that STING is mainly expressed and activated in islet macrophages upon high-fat diet (HFD) feeding. Sting-/- alleviates HFD-induced islet inflammation by inhibiting the expression of pro-inflammatory cytokines and the infiltration of macrophages. Mechanically, palmitic acid incubation promotes mitochondrial DNA leakage into the cytosol and subsequently activates STING pathway in macrophages. Additionally, STING activation in macrophages impairs glucose-stimulated insulin secretion by mediating the engulfment of ß cell insulin secretory granules. Pharmacologically inhibiting STING activation enhances insulin secretion to control hyperglycemia. Together, our results reveal a regulatory mechanism in controlling the islet inflammation and insulin secretion in diet--induced obesity and suggest that selective blocking of the STING activation may be a promising strategy for treating type 2 diabetes.

Hepatocyte CHRNA4 mediates the MASH-promotive effects of immune cell-produced acetylcholine and smoking exposure in mice and humans.

Metabolic dysfunction-associated steatohepatitis (MASH) is a leading risk factor for liver cirrhosis and hepatocellular carcinoma. Here, we report that CHRNA4, a subunit of nicotinic acetylcholine receptors (nAChRs), is an accelerator of MASH progression. CHRNA4 also mediates the MASH-promotive effects induced by smoking. Chrna4 was expressed specifically in hepatocytes and exhibited increased levels in mice and patients with MASH. Elevated CHRNA4 levels were positively correlated with MASH severity. We further revealed that during MASH development, acetylcholine released from immune cells or nicotine derived from smoking functioned as an agonist to activate hepatocyte-intrinsic CHRNA4, inducing calcium influx and activation of inflammatory signaling. The communication between immune cells and hepatocytes via the acetylcholine-CHRNA4 axis led to the production of a variety of cytokines, eliciting inflammation in liver and promoting the pathogenesis of MASH. Genetic and pharmacological inhibition of CHRNA4 protected mice from diet-induced MASH. Targeting CHRNA4 might be a promising strategy for MASH therapeutics.

LncRNAs in non-small cell lung cancer: novel diagnostic and prognostic biomarkers.

Non-small cell lung cancer (NSCLC) is one of the main causes of cancer-related death worldwide, with a serious impact on human health and life. The identification of NSCLC at an early stage is a formidable task that frequently culminates in a belated diagnosis. LncRNA is a kind of noncoding RNA with limited protein-coding capacity, and its expression is out of balance in many cancers, especially NSCLC. A large number of studies have reported that lncRNA acts a vital role in regulating angiogenesis, invasion, metastasis, and the proliferation and apoptosis of tumor cells, affecting the occurrence and development of NSCLC. Abundant evidence demonstrates that lncRNAs may serve as potential biomarkers for NSCLC diagnosis and prognosis. In this review, we summarize the latest progress in characterizing the functional mechanism of lncRNAs involved in the development of NSCLC and further discuss the role of lncRNAs in NSCLC therapy and chemotherapy resistance. We also discuss the advantages, limitations, and challenges of using lncRNAs as diagnostic or prognostic biomarkers in the management of NSCLC.

Menthol induces apoptosis and inhibits proliferation and migration of nonsmall cell lung carcinoma in vitro and in vivo through Akt pathway.

BACKGROUND: About 40% of nonsmall cell lung cancers (NSCLCs) have already progressed in an advanced stage at the time of diagnosis. Development of effective prevention and therapy approaches against NSCLC is critical for reducing mortality. As a fundamental ingredient of peppermint oil, menthol has been demonstrated to possess an antitumor activity in several types of carcinomas. However, the potential role of menthol on NSCLC has not been reported. The present study aims to investigate the effect and underlying mechanism of menthol on proliferation, apoptosis, and mobility of human lung adenocarcinoma. METHODS: Cell apoptosis was examined by MTT and flow cytometry. The motility of cells was determined by Transwell assay. Western blot analysis was performed to determine expression level of proteins. In vivo model of nude mice was established for evaluating the influence of menthol on tumorigenicity of A549 cells. The expression lentiviral vector of Akt was established in NSCLC cells for further verifying the inhibiting effect of menthol on survival and mobility of NSCLC cells via Akt pathway. RESULTS: The results showed that menthol promoted A549 cell apoptosis, suppressed cell proliferation, and motility by altering the phosphorylated protein level of Akt. Menthol enhanced the expression level of Bax while decreasing expression of Bcl-2, Caspase-3, and MMPs proteins. In vivo experiments suggested that menthol exhibited an inhibitory effect in tumor growth on xenografts. These results were further validated in Akt over-expressed A549 and H1299 cells. CONCLUSIONS: Menthol could display an inhibitory effect on NSCLC cells through Akt signaling pathway, making it a potential target for NSCLC treatment.

Knockdown of LIMD2 inhibits the progression of ovarian carcinoma through ERK1/2 pathway.

BACKGROUND: The incidence rate of ovarian carcinoma (OC) is the third of the female reproductive system malignant tumors, while its mortality rate ranks first among causes of female reproductive system tumor related death in the world. METHODS: In the present research, we investigated the specific role of LIMD2 through LIMD2 knockdown in OC cells. RESULTS: The results of online analysis and expression detection proved that LIMD2 was up-regulated in human OC tissues and cells. Knockdown of LIMD2 inhibited the proliferation, migration and invasion in OC cells. LIMD2 knockdown promoted the apoptosis, as well as the expression of Cleaved-Caspase3 and Bax. Importantly, knockdown of LIMD2 promotes cell autophagy. LC3-II/I ratio and Beclin1 expression increased in LIMD2 knockdown cells, while P62 expression declined in LIMD2 knockdown cells. Additionally, the phosphorylation of ERK1/2 was inhibited by the knockdown of LIMD2 in SKOV3 and OVCAR3 cells. CONCLUSION: Knockdown of LIMD2 inhibits cell proliferation, migration, invasion and autophagy, and promotes the apoptosis through the ERK1/2 signaling pathway, suggesting that LIMD2-siRNA may be an effective molecule to prevent OC progression.

Remodeling tumor immunosuppression with molecularly imprinted nanoparticles to enhance immunogenic cell death for cancer immunotherapy.

Insufficient tumor accumulation and distribution of immunogenic cell death (ICD) inducer as well as low antitumor immunity severely restrict the therapeutic efficacy of tumor immunotherapy. Tumor associated fibroblasts (TAFs) are important in tumor extracellular matrix (ECM) remodeling and immune evasion. Reprogramming tumor immunosuppressive microenvironment via TAFs regulation might present a promising way for enhanced ICD effect and complete tumor elimination. In this study, TAFs derived tryptase imprinted nanoparticles (DMSN@MIPs) are developed to modulate TAFs and improve tumor immunotherapy effect of doxorubicin liposomes (DOX/LIP). Tryptase (TPS), secreted by mast cells, are found to support tumor growth via transcriptionally activating TAFs to an activated state with increased expression of fibroblast activation marker α-smooth muscle actin (α-SMA). DMSN@MIPs canbe used as artificial antibodies, which effectively neutralize TPS, reduce TAFs activation, promote intra-tumor penetration of DOX/LIP and enhance ICD effect induced by DOX/LIP. In addition, the combined administration system remodels immunosuppressive microenvironment, which not only significantly up-regulates immune cells (DC cells, CD8+T cells, NK cells), but also significantly down-regulates immunosuppressive cells (Treg cells, MDSCs cells). Our results support the DMSN@MIPs canbe a promising approach to improve ICD efficacy in cancer immunotherapy.

Characterization on nicotine degradation and research on heavy metal resistance of a strain Pseudomonas sp. NBB.

The remediation of polluted sites containing multiple contaminants like nicotine and heavy metals poses significant challenges, due to detrimental effects like cell death. In this study, we isolated a new strain Pseudomonas sp. NBB capable of efficiently degrading nicotine even in high level of heavy metals. It degraded nicotine through pyrrolidine pathway and displayed minimum inhibitory concentrations of 2 mM for barium, copper, and lead, and 5 mM for manganese. In the presence of 2 mM Ba2+ or Pb2+, 3 g L-1 nicotine could be completely degraded within 24 h. Moreover, under 0.5 mM Cu2+ or 5 mM Mn2+ stress, 24.13% and 72.56% of nicotine degradation were achieved in 60 h, respectively. Strain NBB tolerances metal stress by various strategies, including morphological changes, up-regulation of macromolecule transporters, cellular response to DNA damage, and down-regulation of ABC transporters. Notably, among the 153 up-regulated genes, cds_821 was identified as manganese exporter (MneA) after gene disruption and recovery experiments. This study presents a novel strain capable of efficiently degrading nicotine and displaying remarkable resistance to heavy metals. The findings of this research provide valuable insights into the potential application of nicotine bioremediation in heavy metal-contaminated areas.

Single-cell transcriptomics reveals multiple chemoresistant properties in leukemic stem and progenitor cells in pediatric AML.

BACKGROUND: Cancer patients can achieve dramatic responses to chemotherapy yet retain resistant tumor cells, which ultimately results in relapse. Although xenograft model studies have identified several cellular and molecular features that are associated with chemoresistance in acute myeloid leukemia (AML), to what extent AML patients exhibit these properties remains largely unknown. RESULTS: We apply single-cell RNA sequencing to paired pre- and post-chemotherapy whole bone marrow samples obtained from 13 pediatric AML patients who had achieved disease remission, and distinguish AML clusters from normal cells based on their unique transcriptomic profiles. Approximately 50% of leukemic stem and progenitor populations actively express leukemia stem cell (LSC) and oxidative phosphorylation (OXPHOS) signatures, respectively. These clusters have a higher chance of tolerating therapy and exhibit an enhanced metabolic program in response to treatment. Interestingly, the transmembrane receptor CD69 is highly expressed in chemoresistant hematopoietic stem cell (HSC)-like populations (named the CD69+ HSC-like subpopulation). Furthermore, overexpression of CD69 results in suppression of the mTOR signaling pathway and promotion of cell quiescence and adhesion in vitro. Finally, the presence of CD69+ HSC-like cells is associated with unfavorable genetic mutations, the persistence of residual tumor cells in chemotherapy, and poor outcomes in independent pediatric and adult public AML cohorts. CONCLUSIONS: Our analysis reveals leukemia stem cell and OXPHOS as two major chemoresistant features in human AML patients. CD69 may serve as a potential biomarker in defining a subpopulation of chemoresistant leukemia stem cells. These findings have important implications for targeting residual chemo-surviving AML cells.

Chemoproteomic mapping of the glycolytic targetome in cancer cells.

Hyperactivated glycolysis is a metabolic hallmark of most cancer cells. Although sporadic information has revealed that glycolytic metabolites possess nonmetabolic functions as signaling molecules, how these metabolites interact with and functionally regulate their binding targets remains largely elusive. Here, we introduce a target-responsive accessibility profiling (TRAP) approach that measures changes in ligand binding-induced accessibility for target identification by globally labeling reactive proteinaceous lysines. With TRAP, we mapped 913 responsive target candidates and 2,487 interactions for 10 major glycolytic metabolites in a model cancer cell line. The wide targetome depicted by TRAP unveils diverse regulatory modalities of glycolytic metabolites, and these modalities involve direct perturbation of enzymes in carbohydrate metabolism, intervention of an orphan transcriptional protein's activity and modulation of targetome-level acetylation. These results further our knowledge of how glycolysis orchestrates signaling pathways in cancer cells to support their survival, and inspire exploitation of the glycolytic targetome for cancer therapy.

Engineering nanoparticles boost TNBC therapy by CD24 blockade and mitochondrial dynamics regulation.

Although cancer immunotherapy has achieved remarkable progress, the clinical treatment of triple-negative breast cancer (TNBC) is still tough to make a breakthrough. The unsatisfactory therapeutic effect may be attributed to the lack of tumor immunogenicity and the strong immunosuppressive tumor microenvironment (ITM). In order to overcome the above shortcomings, engineering nanoparticles (P-aCD24/CEL + P/shMFN1) was designed to deliver anti-CD24 monoclonal antibody (aCD24), celastrol (CEL) and mitofusin 1 shRNA (shMFN1) for synergistic tumor cells-targeted treatment and tumor-associated macrophages (TAMs)-targeted immunomodulation. CD24, highly expressed on tumor cells, interacts with Siglec10 on TAMs to protect tumor cells from phagocytosis by macrophages, and thus has become a novel and dominant immune checkpoint in TNBC. P-aCD24/CEL achieved the release of aCD24 based on the dual response of carrier to pH and MMP2 in tumor microenvironment. Moreover, CEL increased "eat me" signal CRT and induced the immunogenic cell death (ICD) of tumor cells, together with decreased "don't eat me" signal CD24, reactivated macrophage phagocytosis of tumor cells, and ultimately improves the macrophage-based immunotherapy. On the other hand, P/shMFN1 could target TAMs for mitochondrial dynamics regulation via durable MFN1 silencing in TAMs, thereby reversing the phenotype of M2-TAMs. P-aCD24/CEL and P/shMFN1 could synergistically elicit evident antitumor immune responses and long-term immune memory to significantly inhibit tumor progress and postoperative recurrence. Based on remodeling the ITM and increasing antitumor immune response, this combination immunotherapy strategy showed great potential for TNBC treatment.

Fabrication, Optimization, and Evaluation of Paclitaxel and Curcumin Coloaded PLGA Nanoparticles for Improved Antitumor Activity.

Codelivery of chemotherapeutic drugs in nanoparticles can enhance the therapeutic effects against tumors. However, their anticancer properties and physiochemical characteristics can be severely influenced by many formulation parameters during the preparation process. It is a complicated development phase to select the optimal parameters for preparation of nanoparticles based on the commonly used one single parameter method, which consumes a lot of money, time, and effort, and sometimes even fails. Therefore, the statistical analysis based on Box-Behnken design (BBD) has attracted much attention in bioengineering fields because it can illustrate the influence of parameters, build mathematical models, and predict the optimal combinational factors in a decreased number of experiments. In this study, we used a three-factor three-level BBD design to optimize the preparation of poly(lactic-co-glycolic acid) (PLGA) nanoparticles coloaded with two anticancer drugs curcumin and paclitaxel (PLGA-CUR-PTX nanoparticles). The surfactant concentration, polymer concentration, and oil-water ratio were selected as independent variables. An optimized model of the formulation for PLGA-CUR-PTX nanoparticles was validated. The optimal nanoparticles possessed a uniform spherical shape, with an average size of 99.94 nm, and the drug encapsulation efficiencies of CUR and PTX were 63.53 and 80.64%, respectively. The drug release from nanoparticles showed a biphasic release behavior, with a release mechanism via diffusion and fundamentally quasi-Fickian diffusion. The optimized nanoparticles demonstrated an enhanced cytotoxicity effect with lower IC50 values to 4T1 and MCF-7 breast cancer cell lines compared to free drugs. In summary, BBD optimization of CUR and PTX coloaded nanoparticles yielded a favorable drug carrier that holds potential as an alternative treatment for anticancer therapy.

Reversing ferroptosis resistance by MOFs through regulation intracellular redox homeostasis.

As a non-apoptotic cell death form, ferroptosis offers an alternative approach to overcome cancer chemotherapy resistance. However, accumulating evidence indicates cancer cells can develop ferroptosis resistance by evolving antioxidative defense mechanisms. To address this issue, we prepared a Buthionine-(S,R)-sulfoximine (BSO) loaded metal organic framework (MOF) of BSO-MOF-HA (BMH) with the combination effect of boosting oxidative damage and inhibiting antioxidative defense. MOF nanoparticle was constructed by the photosensitizer of [4,4,4,4-(porphine-5,10,15,20-tetrayl) tetrakis (benzoic acid)] (TCPP) and the metal ion of Zr6, which was further decorated with hyaluronic acid (HA) in order to impart active targeting to CD44 receptors overexpressed cancer cells. BMH exhibited a negative charge and spherical shape with average particle size about 162.5 nm. BMH was found to restore the susceptibility of 4T1 cells to ferroptosis under irradiation. This was attributed to the combination of photodynamic therapy (PDT) and γ-glutamylcysteine synthetase inhibitor of BSO, shifting the redox balance to oxidative stress. Enhanced ferroptosis also induced the release of damage associated molecular patterns (DAMPs) to maturate dendritic cells and activated T lymphocytes, leading to superior anti-tumor performance in vivo. Taken together, our findings demonstrated that boosting oxidative damage with photosensitizer serves as an effective strategy to reverse ferroptosis resistance.