Realveolarization with inhalable mucus-penetrating lipid nanoparticles for the treatment of pulmonary fibrosis in mice.

The stemness loss-associated dysregeneration of impaired alveolar type 2 epithelial (AT2) cells abolishes the reversible therapy of idiopathic pulmonary fibrosis (IPF). We here report an inhalable mucus-penetrating lipid nanoparticle (LNP) for codelivering dual mRNAs, promoting realveolarization via restoring AT2 stemness for IPF treatment. Inhalable LNPs were first formulated with dipalmitoylphosphatidylcholine and our in-house-made ionizable lipids for high-efficiency pulmonary mucus penetration and codelivery of dual messenger RNAs (mRNAs), encoding cytochrome b5 reductase 3 and bone morphogenetic protein 4, respectively. After being inhaled in a bleomycin model, LNPs reverses the mitochondrial dysfunction through ameliorating nicotinamide adenine dinucleotide biosynthesis, which inhibits the accelerated senescence of AT2 cells. Concurrently, pathological epithelial remodeling and fibroblast activation induced by impaired AT2 cells are terminated, ultimately prompting alveolar regeneration. Our data demonstrated that the mRNA-LNP system exhibited high protein expression in lung epithelial cells, which markedly extricated the alveolar collapse and prolonged the survival of fibrosis mice, providing a clinically viable strategy against IPF.

Gamma-aminobutyric acid supplementation improves olanzapine-induced insulin resistance by inhibiting macrophage infiltration in mice subcutaneous adipose tissue.

AIMS: To investigate whether gamma-aminobutyric acid (GABA) supplementation improves insulin resistance during olanzapine treatment in mice and to explore the underlying mechanisms. MATERIALS AND METHODS: Insulin resistance and body weight gain were induced in mice by 10 weeks of olanzapine treatment. Simultaneously, the mice were administered GABA after 4 weeks of olanzapine administration. RESULTS: We found that mice treated with olanzapine had lower GABA levels in serum and subcutaneous white adipose tissue (sWAT). GABA supplementation restored GABA levels and improved olanzapine-induced lipid metabolism disorders and insulin resistance. Chronic inflammation in adipose tissue is one of the main contributors to insulin resistance. We found that GABA supplementation inhibited olanzapine-induced adipose tissue macrophage infiltration and M1-like polarization, especially in sWAT. In vitro studies showed that stromal vascular cells, rather than adipocytes, were sensitive to GABA. Furthermore, the results suggested that GABA improves olanzapine-induced insulin resistance at least in part through a GABAB receptor-dependent pathway. CONCLUSIONS: These findings suggest that targeting GABA may be a potential therapeutic approach for olanzapine-induced metabolic disorders.

Intracavitary Spraying of Nanoregulator-Encased Hydrogel Modulates Cholesterol Metabolism of Glioma-Supportive Macrophage for Postoperative Glioblastoma Immunotherapy.

Glioblastoma multiforme (GBM) is notoriously resistant to immunotherapy due to its intricate immunosuppressive tumor microenvironment (TME). Dysregulated cholesterol metabolism is implicated in the TME and promotes tumor progression. Here, it is found that cholesterol levels in GBM tissues are abnormally high, and glioma-supportive macrophages (GSMs), an essential "cholesterol factory", demonstrate aberrantly hyperactive cholesterol metabolism and efflux, providing cholesterol to fuel GBM growth and induce CD8+ T cells exhaustion. Bioinformatics analysis confirms that high 7-dehydrocholesterol reductase (DHCR7) level in GBM tissues associates with increased cholesterol biosynthesis, suppressed tumoricidal immune response, and poor patient survival, and DHCR7 expression level is significantly elevated in GSMs. Therefore, an intracavitary sprayable nanoregulator (NR)-encased hydrogel system to modulate cholesterol metabolism of GSMs is reported. The degradable NR-mediated ablation of DHCR7 in GSMs effectively suppresses cholesterol supply and activates T-cell immunity. Moreover, the combination of Toll-like receptor 7/8 (TLR7/8) agonists significantly promotes GSM polarization to antitumor phenotypes and ameliorates the TME. Treatment with the hybrid system exhibits superior antitumor effects in the orthotopic GBM model and postsurgical recurrence model. Altogether, the findings unravel the role of GSMs DHCR7/cholesterol signaling in the regulation of TME, presenting a potential treatment strategy that warrants further clinical trials.

Multifunctional biomaterial hydrogel loaded with antler blood peptide effectively promotes wound repair.

Diabetes is an epidemic in contemporary society, which seriously affects people's health. Therefore, it is imperative to develop a multifunctional wound dressing that can expedite the healing of diabetic wounds. In this study, quaternized oxidized sodium alginate (QOSA) and carboxymethyl chitosan (CMCS) formed hydrogel through Schiff base reaction, and the composite hydrogel was prepared by adding the antioxidant activity of deer antler blood polypeptide (D). The hydrogel exhibits favorable attributes, including a high swelling ratio, biocompatibility, and noteworthy antioxidant, antibacterial, and hemostatic properties. Finally, it was used to evaluate its effectiveness in repairing diabetic wounds. Upon evaluation, this hydrogel can effectively promote diabetic wound healing. It facilitates cell proliferation at the wound site, mitigates inflammatory responses, and enhances the expression of growth factors at the wound site. This suggests that this hydrogel holds significant promise as an ideal candidate for advanced wound dressings.

Research Progress of Dihydroquercetin in the Treatment of Skin Diseases.

Skin is a barrier to maintaining the stability of the human environment and preventing the invasion of pathogens. When skin tissue is exposed to the external environment, it will inevitably develop defects due to trauma, injury, burns, ulcers, surgery, and chronic diseases. Rapid skin repair is the key to reducing infection, relieving pain, and improving quality of life. Dihydroquercetin is a kind of flavonoid that has a wide range of pharmacological activities and can improve skin repair, skin inflammation, skin cancer, and so on. In this paper, the application of dihydroquercetin in medical dressings and the research progress in the treatment of skin-related diseases are reviewed, so as to provide reference for further developing dihydroquercetin as a drug for the treatment of skin diseases.

Feasibility and safety of a percutaneous and non-fluoroscopic procedure for left atrial appendage closure in patients for whom fluoroscopy presents risk: a cohort study.

Background: Most patients undergoing left atrial appendage closure (LAAC) are older adult individuals with atrial fibrillation (AF) and many comorbidities, which may elevate the risk for complications associated with contrast agents with the fluoroscopic image-guided procedure. This retrospective cohort study of patients with AF at high risk for use of contrast agents compared the feasibility and safety of LAAC using percutaneous and non-fluoroscopic procedure with transesophageal echocardiography (TEE) as the only image guidance relative to those under fluoroscopic image guidance. Methods: In this retrospective study, we enrolled 126 patients with AF who underwent LAAC from September 2017 to December 2020. Patients were divided into 2 groups based on the imaging guidance modality: a TEE group (n=32) and a fluoroscopic group (n=94). We analyzed the differences in complete closure rates and device- and procedure-related complications between the 2 groups. Continuous variables were assessed using the Student t-test or Mann-Whitney test, while categorical variables were evaluated using Pearson chi-squared test or Fisher exact test. Propensity-score matching was used to adjust for baseline differences. Results: Propensity-score matching yielded 25 pairs of patients with similarly distributed age (72.9±6.9 vs. 73.1±4.9 years; P=0.925), gender (10:15 vs. 11:14; P>0.99), weight (68.3±11.2 vs. 68.1±12.3 kg; P=0.948), and alanine aminotransferase level (20.0±9.8 vs. 22.5±14.2 U/L; P=0.482). The LAA was successfully occluded in all patients, and the TEE group showed similar results to the fluoroscopic group in terms of success rate (100% vs. 100%; P>0.99) and hospitalization duration [5.0 (IQ1-IQ3: 3.0-7.0) vs. 5.0 (IQ1-IQ3: 3.0-6.0) days; P=0.498]. The groups also demonstrated comparable complication rates, with 1 (4.2%) case of pericardial effusion and 1 (4.2%) case of residual shunt in the TEE group, and 5 (20%) cases of residual shunt, 1 (4.2%) case of pericardial effusion, 1 (4.2%) case of myocardial infarction, and 1 (4.2%) case of access-related complications in the fluoroscopic group. There were no deaths. The overall incidence rate of procedure-related complications (6.2% vs. 18.1%, P=0.153) at mean 22.2±4.5 months follow-up between the 2 groups was similar. Conclusions: In patients with AF of high risk for use of contrast agents, LAAC under non-fluoroscopic guidance appears feasible and safe with similar outcomes to that under fluoroscopic guidance.

Population pharmacokinetics of Amisulpride in Chinese patients with schizophrenia with external validation: the impact of renal function.

Introduction: Amisulpride is primarily eliminated via the kidneys. Given the clear influence of renal clearance on plasma concentration, we aimed to explicitly examine the impact of renal function on amisulpride pharmacokinetics (PK) via population PK modelling and Monte Carlo simulations. Method: Plasma concentrations from 921 patients (776 in development and 145 in validation) were utilized. Results: Amisulpride PK could be described by a one-compartment model with linear elimination where estimated glomerular filtration rate, eGFR, had a significant influence on clearance. All PK parameters (estimate, RSE%) were precisely estimated: apparent volume of distribution (645 L, 18%), apparent clearance (60.5 L/h, 2%), absorption rate constant (0.106 h-1, 12%) and coefficient of renal function on clearance (0.817, 10%). No other significant covariate was found. The predictive performance of the model was externally validated. Covariate analysis showed an inverse relationship between eGFR and exposure, where subjects with eGFR= 30 mL/min/1.73 m2 had more than 2-fold increase in AUC, trough and peak concentration. Simulation results further illustrated that, given a dose of 800 mg, plasma concentrations of all patients with renal impairment would exceed 640 ng/mL. Discussion: Our work demonstrated the importance of renal function in amisulpride dose adjustment and provided a quantitative framework to guide individualized dosing for Chinese patients with schizophrenia.

Analysis of lncRNAs profiles associated with ferroptosis can predict prognosis and immune landscape and drug sensitivity in patients with clear cell renal cell carcinoma.

Ferroptosis is a novel kind of iron- and reactive oxygen-induced cell death, investigation into ferroptosis-associated long noncoding RNAs (FALs) in clear cell renal cell carcinoma (ccRCC) is scarce. The goal of the research was to look at FALs' possible predictive significance, as well as their interaction with the immune microenvironment and therapeutic responsiveness of ccRCC. The Cancer Genome Atlas database was employed to retrieve RNA sequencing data from 530 individuals with ccRCC. Patients with ccRCC were randomly assigned to one of two groups: training or testing. Pearson's correlation analysis through the identified ferroptosis-related genes was implemented to screen for FALs. Finally, a FALs signature composed of eight lncRNAs was discovered for predicting survival outcomes in ccRCC patients. ccRCC patients in the training, testing, and overall cohorts were separated into low-risk and high-risk groups based on their risk score. The FALs signature was identified to be an independent factor for overall survival in the multivariate Cox analysis (hazard ratio = 1.013, 95% confidence interval = 1.008-1.018, p < 0.001). A clinically prognostic nomogram was created depending on the FALs signature and clinical characteristics. The nomogram provides greater clinical practicability and may reliably estimate patients' overall survival. The FALs signature may additionally precisely represent ccRCC's immunological environment, immunotherapy reaction, and drug sensitivity. The eight FALs and their signature provide precise and reliable methods for evaluating the clinical effects of in ccRCC patients, and they could be biological markers and targets for therapy.

Deep learning radiomics-based preoperative prediction of recurrence in chronic rhinosinusitis.

Chronic rhinosinusitis (CRS) is characterized by poor prognosis and propensity for recurrence even after surgery. Identification of those CRS patients with high risk of relapse preoperatively will contribute to personalized treatment recommendations. In this paper, we proposed a multi-task deep learning network for sinus segmentation and CRS recurrence prediction simultaneously to develop and validate a deep learning radiomics-based nomogram for preoperatively predicting recurrence in CRS patients who needed surgical treatment. 265 paranasal sinuses computed tomography (CT) images of CRS from two independent medical centers were analyzed to build and test models. The sinus segmentation model achieved good segmentation results. Furthermore, the nomogram combining a deep learning signature and clinical factors also showed excellent recurrence prediction ability for CRS. Our study not only facilitates a technique for sinus segmentation but also provides a noninvasive method for preoperatively predicting recurrence in patients with CRS.

Intracavity generation of glioma stem cell-specific CAR macrophages primes locoregional immunity for postoperative glioblastoma therapy.

Glioblastoma multiforme (GBM) remains incurable despite aggressive implementation of multimodal treatments after surgical debulking. Almost all patients with GBM relapse within a narrow margin around the initial resected lesion due to postsurgery residual glioma stem cells (GSCs). Tracking and eradicating postsurgery residual GSCs is critical for preventing postoperative relapse of this devastating disease, yet effective strategies remain elusive. Here, we report a cavity-injectable nanoporter-hydrogel superstructure that creates GSC-specific chimeric antigen receptor (CAR) macrophages/microglia (MΦs) surrounding the cavity to prevent GBM relapse. Specifically, we demonstrate that the CAR gene-laden nanoporter in the hydrogel can introduce GSC-targeted CAR genes into MΦ nuclei after intracavity delivery to generate CAR-MΦs in mouse models of GBM. These CAR-MΦs were able to seek and engulf GSCs and clear residual GSCs by stimulating an adaptive antitumor immune response in the tumor microenvironment and prevented postoperative glioma relapse by inducing long-term antitumor immunity in mice. In an orthotopic patient-derived glioblastoma humanized mouse model, the combined treatment with nanoporter-hydrogel superstructure and CD47 antibody increased the frequency of positive immune responding cells and suppressed the negative immune regulating cells, conferring a robust tumoricidal immunity surrounding the postsurgical cavity and inhibiting postoperative glioblastoma relapse. Therefore, our work establishes a locoregional treatment strategy for priming cancer stem cell-specific tumoricidal immunity with broad application in patients suffering from recurrent malignancies.

Poly-l-lysine derivative-coated black phosphorus as a nanoplatform for photothermal chemotherapy to enhance anti-tumor efficiency.

Severe systemic toxicity and side effects are major obstacles to the success of chemotherapy for tumors. Regardless of the choice of chemotherapy drugs, the safety of drug delivery materials is crucial, and therefore, there have been various efforts to improve the therapeutic effect and the biological safety of drug delivery systems (DDSs). In this study, a dual stimulus-response DDS (PLL-SS@DOX-BP) was constructed based on the biomaterials of black phosphorus (BP) nanosheets and poly-l-lysine (PLL) to enhance the treatment of doxorubicin hydrochloride (DOX) for breast cancer. The PLL derivative was nano-coated on the surface of drug-loaded BP nanosheets, and it prevented premature leakage of the drug and maintained the stability of the DDS. The introduced disulfide bonds and photothermal agent BP enabled the redox and near-infrared responsive drug release of the DDS, and the coated PLL derivative on the nanocarrier decreased premature leakage of the drug before the DDS reached the tumor tissues. The in vitro and in vivo experiments showed that the combination of biomaterial (PLL) and photothermal material (BP nanosheets) exhibited excellent biological safety and remarkable drug delivery capacity. Moreover, the pharmacodynamic studies indicated that PLL-SS@DOX-BP is a powerful vehicle for photothermal therapy in combination with chemotherapy. Compared with chemotherapy alone, the developed DDS displayed enhanced anti-tumor efficiency with decreased systemic toxicity, and thus, it has the potential to be a promising anti-tumor treatment strategy.

Myeloperoxidase exerts anti-tumor activity in glioma after radiotherapy.

BACKGROUND: Host immune response is a critical component in tumorigenesis and immune escape. Radiation is widely used for glioblastoma (GBM) and can induce marked tissue inflammation and substantially alter host immune response. However, the role of myeloperoxidase (MPO), a key enzyme in inflammation and host immune response, in tumorigenesis after radiotherapy is unclear. In this study, we aimed to determine how post-radiation MPO activity influences GBM and outcome. METHODS: We injected C57BL/6J or MPO-knockout mice with 005 mouse GBM stem cells intracranially. To observe MPO's effects on post-radiation tumor progression, we then irradiated the head with 10 Gy unfractionated and treated the mice with a specific MPO inhibitor, 4-aminobenzoic acid hydrazide (ABAH), or vehicle as control. We performed semi-quantitative longitudinal molecular MRI, enzymatic assays and flow cytometry to assess changes in inflammatory response and tumor size, and tracked survival. We also performed cell culture experiments in murine and human GBM cells to determine the effect of MPO on these cells. RESULTS: Brain irradiation increased the number of monocytes/macrophages and neutrophils, and boosted MPO activity by ten-fold in the glioma microenvironment. However, MPO inhibition dampened radiation-induced inflammation, demonstrating decreased MPO-specific signal on molecular MRI and attenuated neutrophil and inflammatory monocyte/macrophage recruitment to the glioma. Compared to saline-treated mice, both ABAH-treated and MPO-knockout mice had accelerated tumor growth and reduced survival. We further confirmed that MPO decreased tumor cell viability and proliferation in cell cultures. CONCLUSION: Local radiation to the brain initiated an acute systemic inflammatory response with increased MPO-carrying cells both in the periphery and the GBM, resulting in increased MPO activity in the tumor microenvironment. Inhibition or absence of MPO activity increased tumor growth and decreased host survival, revealing that elevated MPO activity after radiation has an anti-tumor role.

Bimetallic metal-organic frameworks for tumor inhibition via combined photothermal-immunotherapy.

Herein, we report the design of therapeutic nanoparticles by encapsulating photosensitizers and aluminum ions into metal-organic frameworks. The nanoparticles could significantly inhibit the growth of primary and rechallenged tumors by a combination of photothermal therapy and immunotherapy. This work offers a promising strategy to design an immunologic nanoplatform for "cold" tumor therapy.

RNA-Seq reveals the potential molecular mechanisms of bovine KLF6 gene in the regulation of adipogenesis.

Marbling influences the taste and tenderness of meat and is the main determinant of carcass quality in many countries. This study aims to investigate the influence of KLF6 (Kruppel Like Factor 6) and associated molecular mechanisms on lipid metabolism in bovine adipocytes. In the current study, KLF6 gene expression was down regulated via siRNA (small interfering RNA) in bovine adipocytes in vitro. Subsequently, adipogenic cells were collected from the culture media after 9 days, and subjected to fluorescent imaging and RNA sequencing. After confirming that KLF6 was down regulated in bovine adipocytes by siRNA, differential gene expression analysis was used to characterize the infuence of KLF6 on gene expression profiles in bovine adipocytes. A total of 10,812 genes were characterized as differentially expressed genes (DEGs) of which, 109 were up-regulated and 62 were down-regulated genes. KEGG (Kyoto Encyclopedia of Genes and Genomes) pathway analysis identified that the DEGs were associated with lipid metabolism, carbohydrate metabolism, cell growth and death, cancer, and the signaling pathways for calcium, AMPK (Adenosine Monophosphate-Activated Protein Kinase), PI3K-Akt (Phosphatidylinositol 3-kinase), PPAR (Peroxisome proliferator-activated receptors), MAPK (mitogen-activated protein kinase), cAMP (Cyclic adenosine monophosphate), and Wnt (Wingless-related integration site). Similarly, gene ontology analysis indicated that down-regulation of KLF6 gene significantly up regulated the genes that regulate adipogenesis, differentiation and regulation of adipocytes and homeostasis of bovine adipocytes, specifically regulating the cell-type specific apoptotic action, negative regulation of apoptotic pathways, programmed cell death, and growth. Results indicate that KLF6 has a role in regulating lipid metabolism in bovine adipocytes. These findings provide evidence that may inform further investigations into molecular mechanisms that underlie the role of bovine KLF6 gene in regulating adipogenesis.

Molecular immuno-imaging improves tumor detection in head and neck cancer.

Detection and accurate delineation of tumor is important for the management of head and neck squamous cell carcinoma (HNSCC) but is challenging with current imaging techniques. In this study, we evaluated whether molecular immuno-imaging targeting myeloperoxidase (MPO) activity, an oxidative enzyme secreted by many myeloid innate immune cells, would be superior in detecting tumor extent compared to conventional contrast agent (DTPA-Gd) in a carcinogen-induced immunocompetent HNSCC murine model and corroborated in human surgical specimens. In C57BL/6 mice given 4-nitroquinoline-N-oxide (4-NQO), there was increased MPO activity in the head and neck region as detected by luminol bioluminescence compared to that of the control group. On magnetic resonance imaging, the mean enhancing volume detected by the MPO-targeting agent (MPO-Gd) was higher than that by the conventional agent DTPA-Gd. The tumor volume detected by MPO-Gd strongly correlated with tumor size on histology, and higher MPO-Gd signal corresponded to larger tumor size found by imaging and histology. On the contrary, the tumor volume detected by DTPA-Gd did not correlate as well with tumor size on histology. Importantly, MPO-Gd imaging detected areas not visualized with DTPA-Gd imaging that were confirmed histopathologically to represent early tumor. In human specimens, MPO was similarly associated with tumors, especially at the tumor margins. Thus, molecular immuno-imaging targeting MPO not only detects oxidative immune response in HNSCC, but can better detect and delineate tumor extent than nonselective imaging agents. Thus, our findings revealed that MPO imaging could improve tumor resection as well as be a useful imaging biomarker for tumor progression, and potentially improve clinical management of HNSCC once translated.

Recent advances of biomimetic nano-systems in the diagnosis and treatment of tumor.

The lack of effective methods of diagnosis and treatment presents a major barrier to combat against tumor. The biomimetic concept is an emerging field that expresses great application potential in tumor fighting. Strategy for combining nano-systems with biomimetic technology has gained increasing attention that is proved bioinspired, environmentally benign, and promising. Herein, we provide an up-to-date review of biomimetic nano-systems as well as their applications in tumor therapy. In addition, the challenges and future directions of biomimetic nano-systems to achieve clinical translation are also pointed out.

The Impact of Smoking, Sex, Infection, and Comedication Administration on Oral Olanzapine: A Population Pharmacokinetic Model in Chinese Psychiatric Patients.

BACKGROUND AND OBJECTIVE: Prior olanzapine population pharmacokinetic (PPK) models have focused on the effects of sex and smoking on olanzapine clearance. This PPK model in Chinese adult psychiatric patients also investigated the influence of comedications and co-occurrence of infections on olanzapine clearance, and explored how to personalize oral olanzapine dosage in the clinical setting. METHODS: A total of 1546 serum concentrations from 354 patients were collected in this study. A one-compartment model with first-order absorption was employed to develop the PPK model using a nonlinear mixed-effects modeling approach. Covariates included demographic parameters, co-occurrence of infection and concomitant medications (including dangguilonghui tablets, a Chinese herbal medicine for constipation). Bootstrap validation (1000 runs) and external validation of 50 patients were employed to evaluate the final model. Simulations were performed to explore the personalization of olanzapine dosing after stratification by sex, smoking, and comedication with valproate. RESULTS: Typical estimates for the absorption rate constant (Ka), apparent clearance (CL/F), and apparent distribution volume (V/F) were 0.30 h-1, 12.88 L/h, and 754.41 L, respectively. Olanzapine clearance was increased by the following variables: 1.23-fold by male sex, 1.23-fold by smoking, 1.23-fold by comedication with valproate, 1.16-fold by sertraline, and 2.01-fold by dangguilonghui tablets. Olanzapine clearance was decreased by the following variables: 0.75-fold by co-occurrence of infection, 0.70-fold by fluvoxamine, and 0.78-fold by perphenazine. The model evaluation indicated that the final model's performance was good, stable, and precise. CONCLUSION: This study contributes to the personalization of oral olanzapine dosing, but further studies should be performed to verify the effects of infection and comedications, including valproate and dangguilonghui.

This study included a total of 1546 serum olanzapine concentrations from 354 Chinese adult psychiatric patients that were analyzed by a complex mathematical model. The goal was to explore how oral olanzapine is eliminated from the body in Chinese psychiatric patients and how to personalize its dosing. Prior studies using similar complex mathematical models only studied the effects of sex and smoking on olanzapine elimination. This study also investigated the influence of co-occurrence of infection and comedications, including dangguilonghui tablets. This is a Chinese herbal medicine used to treat constipation, including constipation secondary to olanzapine treatment. Olanzapine elimination was increased by the following variables: 1.23-fold by male sex, 1.23-fold by smoking, 1.23-fold by comedication with valproate, 1.16-fold by sertraline, and 2.01-fold by dangguilonghui tablets. Olanzapine elimination was decreased by the following variables: 0.75-fold by co-occurrence of infection, 0.70-fold by fluvoxamine, and 0.78-fold by perphenazine. This study contributes to the improvement of oral olanzapine dosing personalization, but further studies are needed to verify the effects of infection and comedications, including valproate and dangguilonghui.

Immunostimulant hydrogel for the inhibition of malignant glioma relapse post-resection.

Immunotherapies have revolutionized intervention strategies for many primary cancers, but have not improved the outcomes of glioblastoma multiforme (GBM), which remains one of the most lethal malignant cerebral tumours. Here we present an injectable hydrogel system that stimulates tumoricidal immunity after GBM surgical resection, which mitigates its relapse. The hydrogel comprises a tumour-homing immune nanoregulator, which induces immunogenic cell death and suppression of indoleamine 2,3-dioxygenase-1, and chemotactic CXC chemokine ligand 10, for a sustained T-cell infiltration. When delivered in the resected tumour cavity, the hydrogel system mimics a 'hot' tumour-immunity niche for attacking residual tumour cells and significantly suppresses postoperative GBM recurrence. Our work provides an alternative strategy for conferring effective tumoricidal immunity in GBM patients, which may have a broad impact in the immunotherapy of 'cold' tumours after surgical intervention.

An ROS-sensitive tegafur-PpIX-heterodimer-loaded in situ injectable thermosensitive hydrogel for photodynamic therapy combined with chemotherapy to enhance the tegafur-based treatment of breast cancer.

Chemotherapy and surgery are commonly used clinical treatments for breast cancer. However, unsatisfactory therapeutic effects, unavoidable side effects, and the removal of breast tissue during surgery are still major obstacles to be overcome during breast-cancer treatment. To overcome the aforementioned issues, a biomimetic and thermosensitive hydrogel encapsulating reactive oxygen species (ROS)-sensitive tegafur (TF)-protoporphyrin IX (PpIX) heterodimers (TTP) was prepared aimed at the strategy of synergizing chemotherapy and photodynamic therapy. TF was grafted onto the photosensitizer PpIX through ROS-sensitive thioether bonds. Under 630 nm laser irradiation, the ROS concentration in tumors was increased to help drug release. The "on-demand" drug release maximized the therapeutic effects of TF and effectively reduced its toxicity. Particularly, the ROS concentration was increased, and it was expected that the tumor-cell-killing abilities of ROS could be exploited. A hydrogel formed from temperature-sensitive chitosan and silk sericin was selected as a drug carrier, which formed a drug reservoir intratumorally after intratumoral injection. Intratumoral injection gave the drug precise and long-term release behavior, which allowed for the clever avoidance of various physical and biological barriers in vivo. In vivo and in vitro studies prove that the use of this TTP hydrogel provides a new attempt to overcome the many difficulties related to breast-cancer treatment simultaneously, and this study opens up new paths for breast-cancer treatment.