Evaluating Oral Probiotic Supplements as Complementary Treatment in Advanced Lung Cancer Patients Receiving ICIs: A Prospective Real-World Study.

OBJECTIVE: To evaluate the effectiveness of oral probiotic supplements in patients undergoing immune checkpoint inhibitors (ICIs) for the treatment of advanced lung cancer. METHODS: This prospective real-world study enrolled patients with advanced lung cancer who were receiving ICIs as part of their treatment. The patients were divided into 2 groups: Group OPS received oral probiotic supplements along with ICIs, while Group C did not. The primary endpoint was progression-free survival (PFS). The secondary outcome measure was the objective response rate (ORR). RESULTS: A total of 253 patients were included in the study, with 71 patients in Group OPS and 182 patients in the control group (Group C). No significant differences were observed in the median PFS between the 2 groups for all patients. However, for small cell lung cancer (SCLC) patients, the median PFS was significantly better in the Group OPS compared to the Group C (11.1 months vs 7.0 months, P = .049). No significant differences were observed in median PFS for the non-small cell lung cancer (NSCLC) cohort between the 2 groups, but a trend towards better median PFS in Group OPS was noticed (16.5 months vs 12.3 months, P = .56). The ORR for the entire cohort was 58.0%. CONCLUSION: Oral probiotics supplements in combination with ICIs included regimen may improve the outcome in patients with advanced SCLC. The above points should be proved by further study.

This study examined whether the addition of oral probiotic supplements to ICIs could enhance the treatment of advanced lung cancer. A total of 253 patients with advanced lung cancer were involved in the study, with some receiving probiotics in combination with ICIs and others not. The findings revealed that patients with SCLC who took probiotics had significantly better PFS compared to those who did not. Additionally, there was a tendency towards enhanced PFS in NSCLC patients who received probiotics. In conclusion, the study indicates that incorporating oral probiotics with ICIs may lead to better outcomes for patients with advanced SCLC, although further research is necessary to validate these results.This real world study explores whether oral probiotic supplements along with immune checkpoint inhibitors (ICIs) can help treat advanced lung cancer. The study included 253 patients with advanced lung cancer receiving ICIs treatment, part of them taking probiotics along with ICIs. The results showed that patients with small cell lung cancer (SCLC) who took probiotics had better progression-free survival (PFS) compared to those who didn't. There was also a trend towards better PFS in non-small cell lung cancer (NSCLC) patients who took probiotics. Overall, the study suggests that taking oral probiotics along with ICIs may improve outcomes for patients with advanced SCLC, but more research is needed to confirm these findings.

Oral exosome-like nanovesicles from Phellinus linteus suppress metastatic hepatocellular carcinoma by reactive oxygen species generation and microbiota rebalancing.

The biomedical application of nanotechnology in cancer treatment has demonstrated significant potential for improving treatment efficiencies and ameliorating adverse effects. However, the medical translation of nanotechnology-based nanomedicines faces challenges including hazardous environmental effects, difficulties in large-scale production, and possible excessive costs. In the present study, we extracted and purified natural exosome-like nanoparticles (ELNs) from Phellinus linteus. These nanoparticles (denoted as P-ELNs) had an average particle size of 154.1 nm, displayed a negative zeta potential of -31.3 mV, and maintained stability in the gastrointestinal tract. Furthermore, P-ELNs were found to contain a diverse array of functional components, including lipids and pharmacologically active small-molecule constituents. In vitro investigations suggested that they exhibited high internalization efficiency in liver tumor cells (Hepa 1-6) and exerted significant anti-proliferative, anti-migratory, and anti-invasive effects against Hepa 1-6 cells. Strikingly, the therapeutic outcomes of oral P-ELNs were confirmed in an animal model of metastatic hepatocellular carcinoma by amplifying reactive oxygen species (ROS) and rebalancing the gut microbiome. These findings demonstrate the potential of P-ELNs as a promising oral therapeutic platform for liver cancer treatment.

Renal damage and old age: risk factors for thrombosis in patients with ANCA-associated vasculitis.

INTRODUCTION: Thrombosis in ANCA-associated vasculitis (AAV) was prevalent and has been neglected in Chinese patients. This study tried to describe the clinical characteristics, identify the risk factors, and investigate the causal relationship between AAV and venous thromboembolism (VTE) by two-sample Mendelian randomization (MR) analysis. METHODS: In this retrospective, observational study, we included all hospitalized AAV patients from Jan 2013 to Apr 2022 in Peking Union Medical College Hospital. We collected their clinical data for multivariate regression analysis to determine the risk factors for thrombosis. The nomogram was constructed by applying these risk factors to predict thrombosis in AAV patients. As for MR analysis, we selected single nucleotide polymorphisms (SNPs) related to AAV from published genome-wide association studies and extracted the outcome data containing deep vein thrombosis (DVT) and pulmonary embolism (PE) from the UK biobank. RESULTS: 1203 primary AAV patients were enrolled, and thrombosis occurred in 11.3%. Multivariate regression suggested that older than 65 years, EGPA, neurological involvement, lung involvement, significantly elevated serum creatinine (> 500µmol/L), and elevated D-dimer were associated with thrombosis in AAV patients. The model demonstrated satisfied discrimination with an AUC of 0.769 (95% CI, 0.726-0.812). MR analysis showed that EGPA could increase the risk of developing DVT and PE (OR = 1.0038, 95%CI = 1.0035-1.0041, P = 0.009). CONCLUSION: Thrombosis was not rare in Chinese patients with AAV. Renal damage and old age emerged as critical risk factors for thrombosis. EGPA might have a potential causal relationship with DVT and PE.

Magnetic natural lipid nanoparticles for oral treatment of colorectal cancer through potentiated antitumor immunity and microbiota metabolite regulation.

The therapeutic efficacy of oral nanotherapeutics against colorectal cancer (CRC) is restricted by inadequate drug accumulation, immunosuppressive microenvironment, and intestinal microbiota imbalance. To overcome these challenges, we elaborately constructed 6-gingerol (Gin)-loaded magnetic mesoporous silicon nanoparticles and functionalized their surface with mulberry leaf-extracted lipids (MLLs) and Pluronic F127 (P127). In vitro experiments revealed that P127 functionalization and alternating magnetic fields (AMFs) promoted internalization of the obtained P127-MLL@Gins by colorectal tumor cells and induced their apoptosis/ferroptosis through Gin/ferrous ion-induced oxidative stress and magneto-thermal effect. After oral administration, P127-MLL@Gins safely passed to the colorectal lumen, infiltrated the mucus barrier, and penetrated into the deep tumors under the influence of AMFs. Subsequently, the P127-MLL@Gin (+ AMF) treatment activated antitumor immunity and suppressed tumor growth. We also found that this therapeutic modality significantly increased the abundance of beneficial bacteria (e.g., Bacillus and unclassified-c-Bacilli), reduced the proportions of harmful bacteria (e.g., Bacteroides and Alloprevotella), and increased lipid oxidation metabolites. Strikingly, checkpoint blockers synergistically improved the therapeutic outcomes of P127-MLL@Gins (+ AMF) against orthotopic and distant colorectal tumors and significantly prolonged mouse life spans. Overall, this oral therapeutic platform is a promising modality for synergistic treatment of CRC.

Mulberry Leaf Lipid Nanoparticles: a Naturally Targeted CRISPR/Cas9 Oral Delivery Platform for Alleviation of Colon Diseases.

Oral treatment of colon diseases with the CRISPR/Cas9 system has been hampered by the lack of a safe and efficient delivery platform. Overexpressed CD98 plays a crucial role in the progression of ulcerative colitis (UC) and colitis-associated colorectal cancer (CAC). In this study, lipid nanoparticles (LNPs) derived from mulberry leaves are functionalized with Pluronic copolymers and optimized to deliver the CRISPR/Cas gene editing machinery for CD98 knockdown. The obtained LNPs possessed a hydrodynamic diameter of 267.2 nm, a narrow size distribution, and a negative surface charge (-25.6 mV). Incorporating Pluronic F127 into LNPs improved their stability in the gastrointestinal tract and facilitated their penetration through the colonic mucus barrier. The galactose end groups promoted endocytosis of the LNPs by macrophages via asialoglycoprotein receptor-mediated endocytosis, with a transfection efficiency of 2.2-fold higher than Lipofectamine 6000. The LNPs significantly decreased CD98 expression, down-regulated pro-inflammatory cytokines (TNF-α and IL-6), up-regulated anti-inflammatory factors (IL-10), and polarized macrophages to M2 phenotype. Oral administration of LNPs mitigated UC and CAC by alleviating inflammation, restoring the colonic barrier, and modulating intestinal microbiota. As the first oral CRISPR/Cas9 delivery LNP, this system offers a precise and efficient platform for the oral treatment of colon diseases.

The prognostic role of gastrointestinal bleeding in patients with a primary gastrointestinal stromal tumor: a long-term follow-up study.

Background: Gastrointestinal (GI) bleeding is one of the common symptoms of GI stromal tumor (GIST). Although several studies have highlighted its prognostic role, conclusions have been inconsistent. This study aimed to investigate the prognosis of GIST patients with GI bleeding. Methods: Primary GIST patients who underwent complete resection and did not receive adjuvant imatinib therapy from January 2003 to December 2008 were reviewed. The Kaplan-Meier method was used to estimate recurrence-free survival (RFS), and multivariate analysis was performed using the Cox proportional hazard model. Propensity score matching (PSM) was conducted to reduce confounders. A systematic review of the published articles in the PubMed, Embase, Cochrane Collaboration, and Medline databases was also conducted, and the inclusion criteria were determined using PICOS (patients, intervention, comparison, outcomes, and study design) principles. Results: In total, 84 patients presenting with GI bleeding and 90 patients without GI bleeding were enrolled in this study. The median time of follow-up was 140 months (range, 10-196 months), and 38 patients developed tumor recurrence/metastasis. For all patients, the multivariate analysis indicated that tumor location [hazard ratio (HR) =3.48, 95% confidence interval (CI): 1.78-6.82, P<0.001], tumor size (HR =1.91, 95% CI: 1.05-3.47, P=0.035), mitotic index (MI; HR =5.69, 95% CI: 2.77-11.67, P<0.001), and age (HR =2.68, 95% CI: 1.49-4.82, P=0.001) were the independent prognostic factors for poor RFS. However, GI bleeding was not associated with RFS (HR =1.21, 95% CI: 0.68-2.14, P=0.518). After PSM, 45 patients from each group were included, and it was found that GI bleeding was still not the independent prognostic factor (HR =1.23, 95% CI: 0.51-2.97, P=0.642). Moreover, the pooled results of our study and six previously reported studies showed that GI bleeding was not the independent prognostic factor (HR =1.45, 95% CI: 0.73-2.86, P=0.287). Conclusions: In this study, tumor location, tumor size, MI, and age were independent prognostic factors in primary GIST patients who underwent radical resection. However, GI bleeding was not associated with worse RFS.

Dual-driven nanomotors enable tumor penetration and hypoxia alleviation for calcium overload-photo-immunotherapy against colorectal cancer.

The treatment efficacies of conventional medications against colorectal cancer (CRC) are restricted by a low penetrative, hypoxic, and immunosuppressive tumor microenvironment. To address these restrictions, we developed an innovative antitumor platform that employs calcium overload-phototherapy using mitochondrial N770-conjugated mesoporous silica nanoparticles loaded with CaO2 (CaO2-N770@MSNs). A loading level of 14.0 wt% for CaO2-N770@MSNs was measured, constituting an adequate therapeutic dosage. With the combination of oxygen generated from CaO2 and hyperthermia under near-infrared irradiation, CaO2-N770@MSNs penetrated through the dense mucus, accumulated in the colorectal tumor tissues, and inhibited tumor cell growth through endoplasmic reticulum stress and mitochondrial damage. The combination of calcium overload and phototherapy revealed high therapeutic efficacy against orthotopic colorectal tumors, alleviated the immunosuppressive microenvironment, elevated the abundance of beneficial microorganisms (e.g., Lactobacillaceae and Lachnospiraceae), and decreased harmful microorganisms (e.g., Bacteroidaceae and Muribaculaceae). Moreover, together with immune checkpoint blocker (αPD-L1), these nanoparticles showed an ability to eradicate both orthotopic and distant tumors, while potentiating systemic antitumor immunity. This treatment platform (CaO2-N770@MSNs plus αPD-L1) open a new horizon of synergistic treatment against hypoxic CRC with high killing power and safety.

Recent advances in mucus-penetrating nanomedicines for oral treatment of colonic diseases.

INTRODUCTION: Oral administration is the most common route for treating colonic diseases that present increased incidences in recent years. Colonic mucus is a critical rate-limiting barrier for the accumulation of oral therapeutics in the colonic tissues. To overcome this obstacle, mucus-penetrating nanotherapeutics have been exploited to increase the accumulated amounts of drugs in the diseased sites and improve their treatment outcomes against colonic diseases. AREAS COVERED: In this review, we introduce the structure and composition of colonic mucus as well as its impact on the bioavailability of oral drugs. We also introduce various technologies used in the construction of mucus-penetrating nanomedicines (e.g. surface modification of polymers, physical means and biological strategies) and discuss their mechanisms and potential techniques for improving mucus penetration of nanotherapeutics. EXPERT OPINION: The mucus barrier is often overlooked in oral drug delivery. The weak mucus permeability of conventional medications greatly lowers drug bioavailability. This challenge can be addressed through physical, chemical and biological technologies. In addition to the reported methods, promising approaches may be discovered through interdisciplinary research that further helps enhance the mucus penetration of nanomedicines.

Clinical characteristics and primary outcomes of patients with ANCA-associated vasculitis and central diabetes insipidus.

Introduction: Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is characterized by systemic small-vessel vasculitis and may rarely present as central diabetes insipidus (CDI). In this study, we aimed to determine the clinical characteristics and prognosis of patients with AAV-associated CDI. Methods: This was a nested case-control study where AAV patients with CDI at the Peking Union Medical College Hospital were followed from January 2012 to April 2022. Case-control matching with AAV patients without CDI was performed (1:5), and participants were matched by age, sex, and AAV classification. We collected clinical data every 3-6 months and conducted a literature review using PubMed to identify relevant articles published from 1983-2022. Results: Among 1203 hospitalized AAV patients, 16 patients with CDI were included (1.3%). The average age was 49 years, and men accounted for 56.3%. Granulomatosis with polyangiitis (GPA) accounted for 87.5% of patients. AAV patients with CDI had more ear, nose, and throat (ENT) (81.3%) involvement and less renal impairment than those in the control group (P<0.05). After a mean follow-up of four years, 50% of patients were in remission from AAV, 37.5% relapsed, and 12.5% died. Our literature review suggested that patients in Asian countries tend to be older men and have higher myeloperoxidase (MPO-ANCA) positivity than those in Western countries. Furthermore, proteinase 3 (PR3-ANCA) positivity may predict disease recurrence. Discussion: AAV patients with CDI had more ENT involvement and a higher eGFR. MPO-ANCA positivity is more commonly observed in Asian countries than Western countries, and PR3-ANCA positivity may predict recurrence.

Screening of core genes and prediction of ceRNA regulation mechanism of circRNAs in nasopharyngeal carcinoma by bioinformatics analysis.

Background: Nasopharyngeal carcinoma (NPC) represents a highly aggressive malignant tumor. Competing endogenous RNAs (ceRNA) regulation is a common regulatory mechanism in tumors. The ceRNA network links the functions between mRNAs and ncRNAs, thus playing an important regulatory role in diseases. This study screened the potential key genes in NPC and predicted regulatory mechanisms using bioinformatics analysis. Methods: The merged microarray data of three NPC-related mRNA expression microarrays from the Gene Expression Omnibus (GEO) database and the expression data of tumor samples or normal samples from the nasopharynx and tonsil in The Cancer Genome Atlas (TCGA) database were both subjected to differential analysis and Weighted Gene Co-expression Network Analysis (WGCNA). The results from two different databases were intersected with WGCNA results to obtain potential regulatory genes in NPC, followed by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) functional enrichment analyses. The hub-gene in candidate genes was discerned through Protein-Protein Interaction (PPI) analysis and its upstream regulatory mechanism was predicted by miRwalk and circbank databases. Results: Totally 68 upregulated genes and 96 downregulated genes in NPC were screened through GEO and TCGA. According to WGCNA, the NPC-related modules were screened from GEO and TCGA analysis results, and the genes in the modules were obtained. After the results of differential analysis and WGCNA were intersected, 74 differentially expressed candidate genes associated with NPC were discerned. Finally, fibronectin 1 (FN1) was identified as a hub-gene in NPC. Prediction of upstream regulatory mechanisms of FN1 suggested that FN1 may be regulated by ceRNA mechanisms involving multiple circRNAs, thereby influencing NPC progression through ceRNA regulation. Conclusion: FN1 is identified as a key regulator in NPC development and is likely to be regulated by numerous circRNA-mediated ceRNA mechanisms.

Dual-stimulus phototherapeutic nanogel for triggering pyroptosis to promote cancer immunotherapy.

Pyroptosis is a highly inflammatory programmed cell death that activates inflammatory response, reverses immunosuppression and promotes systemic immune response for solid tumors treatment. However, the uncontrollable and imprecise process of pyroptosis stimulation leads to a scanty therapeutic effect. Here, we report a GSH/ROS dual response nanogel system (IMs) that can actively target the overexpressed mannose receptor (MR) of cancer cells, serve ultra-stable photothermal capacity of indocyanine green (ICG), induce cell pyroptosis and achieve enhanced tumor immune response. Photo-triggered IMs induce cytoplasmic Ca2+ introgression and activate caspase-3 through photo-activated ICG. The disconnect of SeSe bonds can break the oxidation and reduction balance of tumor cells, causing oxidative stress and synergistically enhancing caspase-3 cleavage, and regulating cell pyroptosis ultimately. Combined with anti-programmed death receptor 1 (anti-PD-1), the nanogel system not only effectivly suppress both primary tumor and distance tumor but also prolong the survival period of mice. This work introduces a strategy to optimize the photothermal performance of ICG and enhances tumor immune response mediated by triggering pyroptosis, which provides an impressive option for immune checkpoint blockade therapy.

Tea leaf-derived exosome-like nanotherapeutics retard breast tumor growth by pro-apoptosis and microbiota modulation.

While several artificial nanodrugs have been approved for clinical treatment of breast tumor, their long-term applications are restricted by unsatisfactory therapeutic outcomes, side reactions and high costs. Conversely, edible plant-derived natural nanotherapeutics (NTs) are source-widespread and cost-effective, which have been shown remarkably effective in disease treatment. Herein, we extracted and purified exosome-like NTs from tea leaves (TLNTs), which had an average diameter of 166.9 nm and a negative-charged surface of - 28.8 mV. These TLNTs contained an adequate slew of functional components such as lipids, proteins and pharmacologically active molecules. In vitro studies indicated that TLNTs were effectively internalized by breast tumor cells (4T1 cells) and caused a 2.5-fold increase in the amount of intracellular reactive oxygen species (ROS) after incubation for 8 h. The high levels of ROS triggered mitochondrial damages and arrested cell cycles, resulting in the apoptosis of tumor cells. The mouse experiments revealed that TLNTs achieved good therapeutic effects against breast tumors regardless of intravenous injection and oral administration through direct pro-apoptosis and microbiota modulation. Strikingly, the intravenous injection of TLNTs, not oral administration, yielded obvious hepatorenal toxicity and immune activation. These findings collectively demonstrate that TLNTs can be developed as a promising oral therapeutic platform for the treatment of breast cancer.

Identification of the miRNA-mRNA regulatory network associated with radiosensitivity in esophageal cancer based on integrative analysis of the TCGA and GEO data.

BACKGROUND: The current study set out to identify the miRNA-mRNA regulatory networks that influence the radiosensitivity in esophageal cancer based on the The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO) databases. METHODS: Firstly, esophageal cancer-related miRNA-seq and mRNA-seq data were retrieved from the TCGA database, and the mRNA dataset of esophageal cancer radiotherapy was downloaded from the GEO database to analyze the differential expressed miRNAs (DEmiRNAs) and mRNAs (DEmRNAs) in radiosensitive and radioresistant samples, followed by the construction of the miRNA-mRNA regulatory network and Gene Ontology and KEGG enrichment analysis. Additionally, a prognostic risk model was constructed, and its accuracy was evaluated by means of receiver operating characteristic analysis. RESULTS: A total of 125 DEmiRNAs and 42 DEmRNAs were closely related to the radiosensitivity in patients with esophageal cancer. Based on 47 miRNA-mRNA interactions, including 21 miRNAs and 21 mRNAs, the miRNA-mRNA regulatory network was constructed. The prognostic risk model based on 2 miRNAs (miR-132-3p and miR-576-5p) and 4 mRNAs (CAND1, ZDHHC23, AHR, and MTMR4) could accurately predict the prognosis of esophageal cancer patients. Finally, it was verified that miR-132-3p/CAND1/ZDHHC23 and miR-576-5p/AHR could affect the radiosensitivity in esophageal cancer. CONCLUSION: Our study demonstrated that miR-132-3p/CAND1/ZDHHC23 and miR-576-5p/AHR were critical molecular pathways related to the radiosensitivity of esophageal cancer.

Surgical resection after orthodontic eruption: A case report of compound odontoma-induced impacted maxillary right central incisor.

Herein, we described the multidisciplinary treatment of a mixed dentition patient with impacted maxillary right central incisor and adjacent compound odontoma. In contrast to conventional treatment procedures, orthodontic traction was first performed for the affected tooth in this case, followed by resection of the odontoma. The odontoma did not shift after eruption of the incisor and was safely removed after alignment of the impacted tooth. No root resorption, gingival recession or bone defect occurred in this case. These results demonstrated that the orthodontic force can break the connection between the impacted tooth and the odontoma. The increased distance between the impacted tooth and odontoma may facilitate removal of the odontoma. Adhesion between the soft tissue capsule of odontoma and the dental follicle, rather than blocking the tooth, may play a role in tooth impaction.

Correction: Biofunctional Janus particles promote phagocytosis of tumor cells by macrophages.

[This corrects the article DOI: 10.1039/D0SC01146K.].

Assembly of Poly(ethylene glycol)ylated Oleanolic Acid on a Linear Polymer as a Pseudomucin for Influenza Virus Inhibition and Adsorption.

Biomimicry of the mucin barrier function is an efficient strategy to counteract influenza. We report the simple aminolyzation of poly(methyl vinyl ether-alt-maleic anhydride) (PM) using amine-terminated poly(ethylene glycol)ylated oleanolic acid (OAPEG) to mimic the mucin structure and its adsorption of the influenza virus. Direct interactions between influenza hemagglutinin (HA) and the prepared macromolecule evaluated by surface plasmon resonance and isothermal titration calorimetry demonstrated that the multivalent presentation of OAPEG on PM enhanced the binding affinity to HA with a decrease in KD of approximately three orders of magnitude compared with monomeric OAPEG. Moreover, hemagglutination inhibition assay, viral growth inhibition assay, and cytopathic effect reduction assay indicated that the nonglycosylated polymer could mimic natural heavily glycosylated mucin and thus promote the attachment of the virus in a subnanomolar range. Further investigation of the antiviral effects via time-of-addition assay, dynamic light scattering experiments, and transmission electron microscopy photographs indicated that the pseudomucin could adsorb the virion particles and synergistically inhibit the early attachment and final release steps of the influenza infection cycle. These findings demonstrate the effectiveness of the macromolecule in the physical sequestration and prevention of viral infection. Notably, due to its structural similarities with mucin, the biomacropolymer also has the potential for the rational design of antiviral drugs, influenza adsorbents, or filtration materials and the construction of model systems to explore protection against other pathogenic viruses.

Bioresponsive immune-booster-based prodrug nanogel for cancer immunotherapy.

The combination of chemotherapy and immunotherapy motivates a potent immune system by triggering immunogenic cell death (ICD), showing great potential in inhibiting tumor growth and improving the immunosuppressive tumor microenvironment (ITM). However, the therapeutic effectiveness has been restricted by inferior drug bioavailability. Herein, we reported a universal bioresponsive doxorubicin (DOX)-based nanogel to achieve tumor-specific co-delivery of drugs. DOX-based mannose nanogels (DM NGs) was designed and choosed as an example to elucidate the mechanism of combined chemo-immunotherapy. As expected, the DM NGs exhibited prominent micellar stability, selective drug release and prolonged survival time, benefited from the enhanced tumor permeability and prolonged blood circulation. We discovered that the DOX delivered by DM NGs could induce powerful anti-tumor immune response facilitated by promoting ICD. Meanwhile, the released mannose from DM NGs was proved as a powerful and synergetic treatment for breast cancer in vitro and in vivo, via damaging the glucose metabolism in glycolysis and the tricarboxylic acid cycle. Overall, the regulation of tumor microenvironment with DOX-based nanogel is expected to be an effectual candidate strategy to overcome the current limitations of ICD-based immunotherapy, offering a paradigm for the exploitation of immunomodulatory nanomedicines.

Atomically Precise Water-Soluble Graphene Quantum Dot for Cancer Sonodynamic Therapy.

Although water-soluble graphene quantum dots (GQDs) have shown various promising bio-applications due to their intriguing optical and chemical properties, the large heterogeneity in compositions, sizes, and shapes of these GQDs hampers the better understanding of their structure-properties correlation and further uses in terms of large-scale manufacturing practices and safety concerns. It is shown here that a water-soluble atomically-precise GQD (WAGQD-C96 ) is synthesized and exhibits a deep-red emission and excellent sonodynamic sensitization. By decorating sterically hindered water-soluble functional groups, WAGQD-C96 can be monodispersed in water without further aggregation. The deep-red emission of WAGQD-C96 facilitates the tracking of its bio-process, showing a good cell-uptake and long-time retention in tumor tissue. Compared to traditional molecular sonosensitizers, WAGQD-C96 generates superior reactive oxygen species and demonstrates excellent tumor inhibition potency as an anti-cancer sonosensitizer in in vivo studies. A good biosafety of WAGQD-C96 is validated in both in vitro and in vivo assays.

Nanotransferrin-Based Programmable Catalysis Mediates Three-Pronged Induction of Oxidative Stress to Enhance Cancer Immunotherapy.

Current oxidative stress amplifying strategies for immunogenic cell death (ICD) promotion are mainly restricted to immune tolerance induced by adaptive cellular antioxidation, limited tumor-selectivity, and tumoral immunosuppression. Herein, a facile and efficient scenario of genetically engineering transferrin-expressing cell membrane nanovesicle encapsulated IR820-dihydroartemisinin nanomedicine (Tf@IR820-DHA) was developed to boost a-PD-L1-mediated immune checkpoint blocking (ICB) via synergetic triple stimuli-activated oxidative stress-associated ICD. We demonstrate that the engineered transferrin of Tf@IR820-DHA has excellent tumor targeting and Fe(III)-loading properties and thus delivered Fe(III) and IR820-DHA nanoparticles (NPs) to the lesion location effectively. We found that the self-carrying Fe(III)-mediated programmable catalysis of DHA and glutathione (GSH) depletion generated plenty of reactive oxygen species (ROS). Moreover, DHA also acted as an immunomodulator to decrease the number of T regulatory cells, thereby remodeling the tumor immune microenvironment and achieving double T cell activation. Furthermore, the IR820 molecule served as a competent sonosensitizer to produce ROS under ultrasound activation and guide precise immunotherapy via fluorescent/photoacoustic (FL/PA) imaging. Through its three-pronged delivery of stimuli-activated oxidative stress (DHA-induced chemodynamic therapy, catalysis-conferred GSH depletion, and IR820-mediated sonodynamic therapy), Tf@IR820-DHA caused high levels of targeted ICD. This significantly increased the proportions of IFN-γ-secreting T cells (CD4+ T and CD8+ T) and enhanced a-PD-L1-mediated ICB against primary and distant tumors, which represents a promising approach for cancer nanoimmunotherapy.

Multi-Responsive Bottlebrush-Like Unimolecules Self-Assembled Nano-Riceball for Synergistic Sono-Chemotherapy.

Improved drug loading content, bioavailability, and controlled release in targeted tissue have been major bottlenecks in the design of precision nanomedicine. Herein, a tumor-specific and multiple-stimuli responsive nano-riceball is proposed and validated for enhanced sono-chemotherapy. The nano-riceball (NGR@DDP) possesses a well-designed core-shell structure, formed by an inner core assembly that contains ultrasound/H2 O2 responsive bottlebrush-like unimolecular dextran-POEGMA9 -b-PMTEMA22 (DOS) with co-loaded doxorubicin and Purpurin 18. This inner core of NGR@DDP is further buried by a "striffen" of NGR (Asn-Gly-Arg)-modified RBC-membrane derived from CRISPR-engineered mice. As a result, nano-riceball NGR@DDP is featured with high drug stuffing content (30.3 wt%), low critical micelle concentration (5.93 µg mL-1 ), and intelligent exogenous ultrasound/endogenous H2 O2 stimuli-triggered precise drug release at tumor site. Under fluorescence/photoacoustic imaging guidance, combined sonodynamic therapy and chemotherapy exhibit excellent synergistic effect, and dramatically inhibit the growth of orthotopic HepG2 hepatocellular carcinoma with negligible side effects. This nano-riceball strategy provides a facile way to achieve function hybridization for personalized nanomedicine.