Doping plays a crucial role in both electrical and optical properties of semiconductors. In this work, we report observation, as well as optical control, of the fluorescence spatial hole burning effect in monolayer WS 2 . We demonstrate that the pronounced exciton-exciton annihilation process, in combination with the efficient capture of holes by intrinsic sulfur vacancy defects, induces a significant photo-doping effect and eventually leads to fluorescence spatial hole burning. By means of a dual-beam pumping fluorescence imaging technique, we reveal that the recovery process of the spatial hole burning effect exhibits a double-exponential behavior. The fast recovery process originates from the release of trapped holes under the illumination of the probe beam, while the slow process corresponds to the re-adsorption of electronegative gas molecules. Surprisingly, our results demonstrate that the electronegative sulfur vacancies can achieve ultralong-term storage of holes. Moreover, both the release and the rate of release of holes can be fully controlled by laser irradiation. These findings demonstrate the great potential of transition metal dichalcogenides in the development of optically-control excitonic devices.

Although stimulating microglia to phagocytose abnormally infiltrated cells and tissue debris is crucial for improving the prognosis of ischemic stroke, this energy-intensive physiological process is hindered by the cerebral artery block-induced oxygen/ glucose deprivation. AMP-activated protein kinase (AMPK), as a key molecule regulating energy metabolism, shows promise in resolving this dilemma by elevating intracellular ATP levels in microglia. Here, we uncovered that while activation of AMPK can enhance energy metabolism, it also induces mitochondrial damage via reactive oxygen species (ROS), which demonstrates its double-edged effect. Based on this, we have developed a systematic screening paradigm consisting of a molecular simulation prediction - real-world validation - disease model treatment axis. From the library of natural polyphenols, gallic acid and ellagic acid were screened for their ability to effectively activate AMPK and scavenge ROS, and exhibit therapeutic effects in a photothrombotic (PT) stroke model. To overcome the poor bioavailability and targeting capability of natural polyphenols, we constructed a class of metal-organic frameworks (MOFs) as neuroprotective agents, which are formed by coordinating gallic acid with metal ions. Microglia benefiting from these MOFs exhibit more efficient phagocytosis, lower ROS levels, and higher cell viability. In a PT stroke model, stereotaxic injection of MOFs significantly increased microglial phagocytosis, provided superior neuronal protection, and improved behavioral outcomes. This strategy highlights the potential of natural polyphenols as neuroprotective agents and emphasizes the complexity and feasibility of regulating microglial phagocytosis via AMPK activation to promote stroke recovery, offering valuable insights into improving prognosis.

Parastomal hernia (PSH) is one of the most frequent long-term complications following abdominoperineal resection (APR) for rectal cancer. The optimal colostomy route to minimize PSH remains controversial. This study aimed to compare PSH risk between extraperitoneal colostomy (EPC) and transperitoneal colostomy (TPC) after laparoscopic APR. A retrospective cohort study was conducted including patients who underwent laparoscopic APR for rectal cancer between 2014 and 2017. Patients were categorized according to colostomy route (EPC vs. TPC). The primary endpoint was PSH, and secondary endpoints included other short- and long-term stoma-related complications and perioperative outcomes. Propensity score matching (1:3) was applied to balance baseline characteristics. Risk factors for PSH were further analyzed using logistic regression. A total of 464 patients were included. After matching, 102 patients in the EPC group and 243 in the TPC group were analyzed. Perioperative outcomes and overall stoma-related complication rates were comparable between groups. However, PSH occurred less frequently in the EPC group than in the TPC group (10/102 [9.8

A superior-performance NH3 sensor was prepared with ultrathin g-C3N4/CeO2 composites with plentiful oxygen vacancies, and the sensing mechanism was elucidated through first-principles calculations. The results of the experiment reveal that When exposed to 500 ppm NH3 at RT, the g-C3N4/CeO2 sensor achieves a response value of 2376.95, which is 11.15 times greater than that of the single CeO2 sensor. Furthermore, the times for response/recovery toward 50 ppm NH3 are 3/1 s, and the experimental detection limit of g-C3N4/CeO2 is 1 ppm, respectively. The g-C3N4/CeO2 exhibits excellent sensitivity and humidity resistance in NH3 detection, which is mainly rooted in the increased oxygen vacancies and the reduced hydrophilic -OH and -NH2 groups on the g-C3N4/CeO2 surface. Density functional theory (DFT) computations confirm that the heterostructure assembly of ultrathin g-C3N4 and CeO2 via N-Ce bonds generates abundant oxygen vacancies on the CeO2 surface, while contributing to the bonding between electrons in the d orbitals of Ce atoms and the lone-pair electrons of NH3. In addition, the synergistic effect between CeO2 and g-C3N4 gives rise to a higher adsorption energy for NH3 than for other gases, indicating its excellent sensing performance toward NH3. Eventually, the g-C3N4/CeO2 NH3 sensor achieves effective simulated detection of kidney diseases. This study provides a non-invasive, rapid and accurate detection method for the early diagnosis of renal diseases.

Irinotecan is a widely used chemotherapeutic agent for the treatment of advanced and metastatic colorectal cancer (CRC). However, its clinical application remains unsatisfactory due to its side effects and limited efficacy. Here, we first demonstrate that irinotecan promotes liver metastasis in CRC by inducing chemotherapy-related steatohepatitis, which is an understudied side effect of irinotecan. To abrogate the prometastatic effect of irinotecan, we employ indole-3-carbinol (I3C), an aryl hydrocarbon receptor (AHR) agonist, to develop a self-assembled nanomedicine (termed NICER). NICER abolishes liver metastasis driven by irinotecan-induced steatohepatitis through activating the AHR/CPT1A axis and promoting fatty acid oxidation of hepatocytes. Importantly, NICER also significantly potentiated the antitumor effect of irinotecan. It markedly enhances cellular uptake of irinotecan via caveolin-dependent endocytosis, enabling direct delivery to the endoplasmic reticulum (ER) to induce lethal ER stress. Meanwhile, I3C encapsulated in NICER inhibits glycolysis by activation of AHR. In subcutaneous and liver metastatic CRC models, NICER demonstrates potent antitumor efficacy, reducing the tumor burden by 74.6% and 96.2%, respectively, while also exhibiting good biosafety. In summary, this work synergistically abrogates the prometastatic adverse effect of irinotecan and enhances its antitumor efficacy, presenting a promising strategy to potentiate irinotecan-based chemotherapies.

ETHNOPHARMACOLOGICAL RELEVANCE:Recurrence and metastasis significantly impact the survival outcomes of gastric cancer (GC) patients. Weifuchun (WFC), a well-established traditional Chinese medicine formulation, has been widely used in clinical practice for treating gastric disorders and as an adjunctive therapy following GC surgery. AIM OF THE STUDY:Despite its extensive use, the efficacy and underlying mechanisms of WFC in reducing recurrence and metastasis in GC patients remain poorly understood. MATERIALS AND METHODS:We evaluated the effect of WFC combined with chemotherapy on the disease-free survival (DFS) in patients with stage II and III GC following radical surgery through a randomized and controlled trial. miRNA expression profiles were assessed via miRNA arrays. Target genes of miR-139-5p were predicted using TargetScan, miRDB, miRTarBase and miRWalk databases. The overall survival (OS) associated with miR-139-5p and its target gene CXCR4 was analyzed using TCGA data. The anti-proliferative effect was evaluated in vitro using the CCK-8 assay. Angiogenesis-related functions were assessed using HUVECs transwell migration, tube formation, and adhesion assays. Protein and gene expression levels were measured using Western blot and qRT-PCR. Immunocytochemistry was performed to detect the expression and localization of CD31 and CXCR4. Fluorescence in situ hybridization (FISH) was employed to determine miR-139-5p expression and localization. Reporter assays were used to measure luciferase activity of both wild-type and mutant CXCR4 3'UTR. RESULTS:The combination of WFC and chemotherapy significantly extended DFS in stage II and III GC patients post radical surgery. miR-139-5p expression was upregulated in 32 GC serum samples post-WFC plus chemotherapy, compared to 31 GC serum samples post-chemotherapy treatment. A similar upregulation was observed in vitro in WFC-treated HUVECs compared with untreated HUVECs. Reduced miR-139-5p expression in stage II and III GC tissues and serum was associated with disease progression, metastasis, and vascular infiltration. Functionally, WFC dose-dependently inhibited HUVEC proliferation, tube formation, migration, invasion, and adhesion. Mechanistically, suppression of miR-139-5p or increased CXCR4 expression diminished WFC's anti-angiogenic effects. Additionally, CXCR4 was confirmed as a target gene of miR-139-5p. In preclinical models, the combination of WFC and 5-fluorouracil (5-Fu) exerted a synergistic effect in suppressing tumor growth in a GC subcutaneous xenograft model; whereas in a GC liver metastasis model, WFC inhibited 5-Fu-induced metastasis and invasion. Naringin, a core active component of WFC, exhibited potent antiproliferative activity, as well as anti-migratory and anti-metastatic capacities in GC cells within a safe dose range. CONCLUSIONS:WFC shows promise in benefiting patients with stage II and III GC. Through its modulation of the miR-139-5p/CXCR4 axis, WFC serves as a potent inhibitor of angiogenesis, potentially enhancing the effectiveness of chemotherapy while reducing GC recurrence and metastasis.

Surgery is the mainstay of treatment for patients with solid tumors. However, the intricate inflammatory and immunosuppressive tumor microenvironment after surgery is recognized as a primary cause of tumor recurrence and metastasis. Here, we design and construct an in situ injectable therapeutic hydrogel encapsulating 1-methyl-d-tryptophan (1-d-MT), a small-molecule competitive inhibitor of indoleamine 2,3-dioxygenase, and meloxicam, a selective inhibitor of cyclooxygenase-2 (Ge1MT/Mel hydrogel) to prevent postoperative tumor metastasis and relapse. In this hydrogel system, 1-d-MT increases cytotoxic T lymphocytes and decreases regulatory T cells, thereby reversing the tumor immune tolerance microenvironment, while released meloxicam reduces inflammation caused by postoperative trauma via the COX-2/PGE2 pathway. When delivered into the resected tumor cavity, the hydrogel system mimics a "hot" tumor-immunity niche to attack residual tumor cells and significantly suppresses the postoperative recurrence of colorectal cancer. In the model of postoperative breast cancer and colorectal cancer recurrence and metastasis, the Ge1MT/Mel hydrogel substantially reduces the volume of recurrent tumors and demonstrates 85.1% and 66.7% inhibition rates of metastases, respectively. Importantly, the Ge1MT/Mel hydrogel markedly stimulates a potent antitumor immune response in the cancer lesion microenvironment, increasing antitumor immune cells including CD8+ T cells, as well as elevating antitumor cytokines such as interferon-γ. Overall, combination immunotherapy via the Ge1MT/Mel hydrogel after surgery represents a promising strategy to minimize residual tumor burden and reduce recurrence risk following tumor resection.

Background: Conventional laparoscopic-assisted surgery (CLS) for sigmoid and upper rectal cancer requires an abdominal extraction incision, linked to pain, surgical site infection and poor cosmesis. Natural orifice specimen extraction surgery (NOSES) removes tumours via the anus without abdominal wounds, yet high-quality randomised controlled trial evidence on long-term oncological safety remains scarce. This multicentre trial aimed to verify whether NOSES is non-inferior to CLS regarding 3-year disease-free survival (DFS), alongside evaluating short-term recovery and complications. Methods: This open-label, parallel-group, non-inferiority randomised trial enrolled patients with cT1-3N0-2M0 sigmoid/upper rectal adenocarcinoma across 13 Chinese tertiary centres between Aug 30, 2020, and Nov 5, 2023. Participants were 1:1 allocated via centre-stratified web randomisation; outcome assessors at discharge were masked to group assignment. The prespecified non-inferiority margin for 3-year DFS was 10%. Primary analysis used the modified intention-to-treat (mITT) population; per-protocol (PP) data served for sensitivity analysis. Trial registration: ChiCTR2000036314. Findings: 516 patients were randomised (258 per group). The mITT survival cohort included 205 CLS and 208 NOSES participants, with median follow-up of 36.9 months. 3-year DFS was 89.7% (95% CI 85.1-94.6) for CLS and 94.7% (91.1-98.4) for NOSES (absolute difference 5.0%, 95% CI -3.4 to 13.3, meeting non-inferiority; log-rank p=0.088). 3-year overall survival and local recurrence rates were similar between groups. NOSES patients had earlier first flatus (p<0.001), lower postoperative NRS pain scores, and less rescue analgesic use (17.5% vs 37.4%, p<0.001). Overall 30-day complication rate was numerically lower in NOSES (12.0% vs 18.3%, p=0.056); all incisional surgical site infections occurred only in the CLS group (6.0%). Hospital costs were higher with NOSES (mean difference 6525 CNY, p<0.001). No 30-day deaths occurred in either arm. Interpretation: For selected patients with cT1-3N0-2M0 sigmoid or upper rectal cancer, NOSES performed by experienced surgeons delivers non-inferior long-term oncological outcomes versus CLS, with meaningful improvements in postoperative pain, bowel recovery and surgical site infection risk. NOSES represents a patient-friendly minimally invasive option for suitable candidates.

Osteoarthritis (OA) is a chronic, whole-joint degenerative disease that ultimately leads to joint deformity and permanent loss of function. Chondrocyte dysfunction secondary to inflammatory responses and oxidative stress impedes the regenerative remodeling of cartilage. Here, a kind of cartilage-adhesive/penetrating self-assembled nanoparticles (GE NPs) are constructed through multiple dynamic covalent and non-covalent interactions between epigallocatechin gallate (EGCG) and glucosamine (GlcN). The hydrogen bonding interactions between GE NPs and the cartilage surface mediate their prolonged retention within the joint cavity. The optimized particle size allows GE NPs to readily penetrate the fibrous matrix of cartilage, facilitating deep tissue delivery. GE NPs reverse OA progression by scavenging reactive oxygen species (ROS) and regulating macrophage polarization, thereby establishing an anti-inflammatory microenvironment and rescuing chondrocytes from apoptosis. Simultaneously, pH-responsive GlcN release promotes the synthesis and secretion of proteoglycans, thereby enhancing cartilage matrix regeneration in the inflammatory microenvironment. In vivo experiments demonstrate that GE NPs facilitate cartilage regeneration and alleviate OA progression within one month. Overall, this cartilage-adhesive, deeply penetrating, and pH-responsive nanoplatform for the co-delivery of GlcN and EGCG represents a synergistic approach to OA treatment.

BACKGROUND AND AIMS:Conventional body composition assessment fails to capture its multidimensional complexity in gastric cancer (GC). This study aimed to systematically evaluate multidimensional body composition and its clinical relevance in GC. METHODS:1196 GC patients and 983 healthy controls were retrospectively enrolled. Body composition was segmented using nnU-Net. Propensity score matching was used to compare body composition differences between patients and healthy controls. Prognostic value was assessed across treatment cohorts. TCGA pathological and transcriptomic data were integrated for exploratory analyses. Sex-specific prognostic models were developed and externally validated. RESULTS:AI-drived body compositions parameters showed sex-specific associations with survival. Higher muscle/fat area/index and lower fat density correlated with longer survival in surgical patients (L1 muscle area: HR = 0.438, ad p = 0.001). In ICI-treated females, higher subcutaneous fat area (SFA) improved survival (L2SFA: HR = 0.972, ad p = 0.045). Potential associations were observed between body composition and tumor microenvironmental features, including stromal composition, EMT-related pathways, and immune infiltration. Sex-specific prognostic models achieved C-indices of 0.723 (males) and 0.705 (females) in test cohorts, outperforming conventional predictors. CONCLUSION:Multidimensional body composition is associated with prognosis in GC and may serve as a complementary biomarker for risk stratification.

L-arginine (L-Arg) deprivation in the tumor microenvironment (TME) drives effector T cell dysfunction and immunotherapy resistance. However, simply supplementing L-Arg can be counterproductive, as tumor cells and immunosuppressive myeloid cells act as dominant consumers, co-opting the nutrient to promote tumor progression. To break this detrimental cycle without fueling protumoral networks, we develop a near-infrared (NIR)-triggered nanoregulator (hPFL@Lipo) to simultaneously alleviate intratumoral L-Arg deficiency and redirect its metabolism to support antitumor immunity. This nanoregulator was constructed through coordination-driven self-assembly to co-load and stabilize L-Arg and Fe3+ within hollow Prussian blue (hPB) nanoparticles, followed by lipid membrane encapsulation for enhanced systemic stability. Under NIR irradiation, hPFL@Lipo releases Fe3+ and L-Arg while generating localized hyperthermia. Fe3+ repolarizes M2-like macrophages toward an M1 phenotype, thereby increasing the intratumoral M1-to-M2 ratio. The photothermal effect induces immunogenic tumor cell death, which promotes the infiltration of cytotoxic CD8+ T cells. Concurrently, the released L-Arg supplements the local pool, while thermal ablation reduces the overall cellular burden within the tumor, thereby alleviating arginine local depletion. Together, this strategy resolves the tumor–immune conflict over L-Arg by remodeling the intratumoral landscape of L-Arg consumers in favor of antitumor effector cells, thereby reprogramming the net metabolism of the tumor from a tumor-promoting to a tumor-suppressing state and achieving potent synergy with αPD-1 therapy.

Basal-type muscle-invasive bladder cancer (BMIBC) is characterized by aggressive metastasis and poor prognosis but lacks molecularly defined therapeutic targets. Through integrative analyses of clinical cohorts and BBN-induced mouse models, we identified KRT14 as a core oncogenic driver that orchestrates the KRT14-IGF2BP1 signaling axis to promote BMIBC progression and lung metastasis. Mechanistically, residues K294 and E295 within the KH2 domain of IGF2BP1 specifically recognize conserved residues D226 and E227 within the nuclear export signal of KRT14. This direct interaction facilitates IGF2BP1-mediated cytoplasmic trafficking and auto-stabilization of its own mRNA, establishing a positive feedback loop that amplifies IGF2BP1-targeted pro-invasive gene expression. Functional disruption of this axis suppressed primary tumor progression and lung metastasis in BMIBC models. Collectively, our findings define the KRT14-IGF2BP1 axis as a previously unrecognized, potentially targetable vulnerability in BMIBC, whose inhibition may limit aggressive disease progression and inform future therapeutic strategies.

Oxaliplatin (L-OHP) is a first-line chemotherapeutic agent for both advanced colorectal cancer (CRC) and postoperative adjuvant therapy. However, the development of acquired L-OHP resistance remains a major clinical obstacle. Here, we identify Tubocapsenolide A (TA), a natural withanolide isolated from Tubocapsicum anomalum , as a potent antitumor agent that not only suppresses CRC growth but also effectively reverses acquired L-OHP resistance. Using a PROTAC-based target deconvolution strategy combined with biophysical validation, we demonstrate that PLK1 is the direct functional target of TA. PLK1 is aberrantly overexpressed in L-OHP-resistant CRC and negatively correlates with patient sensitivity to L-OHP. Mechanistically, overexpressed PLK1 hyperphosphorylates the adaptor protein CEP55 to recruit the ESCRT machinery, driving a previously unappreciated PLK1-CEP55-ESCRT-dependent vesicular extrusion process. This enables resistant cells to rapidly clear L-OHP-induced damage through γ-H2A.X⁺ nuclear budding and TOM20⁻/PDH⁺ mitochondrial-derived vesicles, thereby preserving organelle integrity and promoting cell survival. By directly binding and inhibiting PLK1, TA disrupts the CEP55-ESCRT-dependent membrane scission machinery, leading to intracellular accumulation of damaged components. Consequently, it triggers severe nucleolar stress and mitochondrial dysfunction, ultimately inducing death in L‑OHP‑resistant cells. Collectively, our findings uncover a novel PLK1-CEP55-ESCRT-driven vesicular extrusion mechanism underlying L-OHP resistance and establish targeting this axis as a promising therapeutic strategy for chemorefractory CRC. TA represents a valuable lead compound for the development of new treatments against L-OHP-resistant CRC.

Background Long non-coding RNAs (LncRNAs), functioning as competitive endogenous RNAs (ceRNAs), are pivotal in the onset and progression of hepatocellular carcinoma (HCC). Although DSCAM-AS1 is recognized as an oncogenic LncRNA, its ceRNA mechanism in HCC is not yet fully understood. Objective This study aims to investigate the molecular mechanism by which LncRNA DSCAM-AS1 influences the proliferation of hepatocellular carcinoma (HCC) cells via the ceRNA network. Additionally, it seeks to identify the crucial downstream genes and their associated signaling pathways in HCC. Methods We identified differentially expressed genes using RNA-seq data from the TCGA-LIHC database. The target genes of miR-124-3p were predicted through miRDB and TargetScan, leading to the construction of a DSCAM-AS1-miR-124-3p-mRNA regulatory network. Key pathways were identified via KEGG enrichment analysis. Expression and prognostic analyses were conducted using GEPIA. To verify the causal relationship between candidate genes and the risk of HCC, we employed the two-sample Mendelian randomization (MR) method. Results We identified 78 differentially expressed mRNAs regulated by miR-124-3p and constructed a ceRNA network with DSCAM-AS1 as the central node. Functional enrichment analysis revealed that these mRNAs are significantly enriched in proliferation-related pathways, including the cell cycle, PI3K-AKT, and MAPK. MR analysis confirmed a significant negative causal relationship between ANAPC7 and HCC risk (IVW p < 0.05), with high ANAPC7 expression linked to poor patient prognosis. Similarly, CDK4 was highly expressed in HCC and correlated with prognosis. Conclusion LncRNA DSCAM-AS1 may sequester miR-124-3p, alleviating its suppression of crucial genes like ANAPC7 and CDK4. This interaction potentially activates signaling pathways, including the cell cycle, thereby enhancing the proliferation and progression of HCC. This study offers a novel perspective on ceRNA regulation in the molecular mechanisms of HCC and identifies potential therapeutic targets.

Multiple primary colorectal cancer (MPCRC) is uncommon but clinically challenging, and differences between synchronous MPCRC (SMPCRC) and metachronous MPCRC (MMPCRC) remain incompletely defined. We compared clinicopathological and surgical features between SMPCRC and MMPCRC and explored prognostic factors for overall survival (OS) in MPCRC. This retrospective cohort study consecutively included patients with pathologically confirmed multiple primary colorectal adenocarcinoma who underwent curative-intent resection at our hospital. SMPCRC was defined as tumors identified within 6 months and MMPCRC as a subsequent primary diagnosed after 6 months. Clinicopathological and perioperative variables were extracted from medical records and pathology reports. Mismatch repair protein expression was assessed as an exploratory pathological variable. OS was analyzed using Kaplan–Meier methods and Cox proportional hazards regression. A total of 165 patients were included (120 SMPCRC and 45 MMPCRC) with follow-up until December 2024. Baseline characteristics were broadly comparable between groups. SMPCRC more frequently underwent laparoscopic surgery (97.5

The upregulation of PD-1 on T lymphocytes is one of the key mechanisms driving sepsis-induced immunosuppression. Nevertheless although it is known that PD-L1 on antigen-presenting cells acts as a ligand for PD-1 on T lymphocytes, it remains to be determined whether extracellular vesicle-associated PD-L1 also serves as its ligand. Plasma extracellular vesicles (EVs) were isolated via ultracentrifugation. We evaluated the relationship of EV-associated PD-L1 level to immune function and prognosis in septic patients. Additionally, we observed the effect of EV-associated PD-L1 on the proliferation and immune function of co-cultured CD4+ T cells in vitro. We further verified the role of EV-associated PD-L1 by knocking down PD-L1 in a mouse model. The peripheral circulating EV levels were significantly increased in septic patients compared with healthy volunteers. Enhanced PD-L1 protein content on these EVs was evident in septic patients, particularly in those exhibiting adverse prognostic features and pronounced immunosuppression. EVs secreted by LPS-stimulated monocytes were enriched with more PD-L1 than monocytes alone. Co-culture of CD4+ T cells with sepsis-derived EVs significantly downregulated the expression of CD69, IFN-γ and cell viability but upregulated the level of IL-4 and TGF-β. This was accompanied by heightened PD-1 expression and an increased Tregs/CD4+ T cell ratio. Conversely, this effect was partially reversed by inhibition of EV production or knockout of PD-L1 in EVs. Compared with LPS-treated EVs, PD-L1 knockout LPS-treated EVs alleviated the immunosuppressive state in CLP mice. The elevated level of circulating EV-associated PD-L1 was closely associated with poor prognosis and immunosuppression in septic patients. EV-associated PD-L1 engaged CD4+ T cells to induce CD4+ T cell dysfunction and may be one of the key mechanisms inducing immunosuppression in sepsis.

361 Background: Neoadjuvant chemoimmunotherapy is revolutionizing the treatment landscape for solid tumors. However, a subset of patients exhibited limited therapeutic response. Metabolomic profiling of non-responding patients revealed aberrant polyol pathway activation, with sorbitol accumulation identified as a novel immune-modulatory mechanism. To address this challenge , we initiated a randomized controlled trial evaluating the safety and efficacy of chemoimmunotherapy combined with a sorbitol-restricted diet in locally advanced gastric cancer (LAGC) patients. Methods: Key inclusion criteria were: age ≥ 18 years; histologically confirmed gastric cancer with locally advanced disease as defined by the AJCC 8th Edition; and no prior systemic anticancer therapy. Eligible patients were randomized 1:1 to receive either neoadjuvant chemoimmunotherapy (3-week cycles of SOX plus PD-1 antibody tislelizumab) combined with sorbitol-supplemented diet (2 g per dose, three times daily during treatment weeks； intervention group), or neoadjuvant chemoimmunotherapy (control group). The primary endpoint was the major pathological response (MPR) rate. Secondary endpoints included pathological complete response (pCR) rate, disease control rate (DCR), and R0 resection rate. Exploratory endpoints included treatment-related adverse events (TRAEs), progression-free survival (PFS), and overall survival (OS). Clinical trial registration: NCT06826079. Results: This interim analysis included the first 26 patients (13 per arm) of a planned 86-patient cohort. Demographic characteristics were comparable between groups, with the investigational arm comprising 8 males and 5 females (mean age 59 years, range 45-72) and the control arm 9 males and 4 females (mean age 56 years, range 48-68). Gastric signet ring cell carcinoma (GSRCC), prevalence showed a numerical trend favoring the investigational arm (46.2% vs 30.8%, p=0.42). Both groups demonstrated identical pCR rates (23.1%, 3/13 per arm), but the investigational arm exhibited superior MPR rates (61.5% vs 38.5%, p=0.039) and significantly higher ypN0 status achievement (76.9% vs 38.5%, p=0.012), with the GSRCC subgroup showing similar trends (MPR: 50% vs 25%; ypN0: 67.7% vs 25%). Both groups maintained 100% R0 resection and DCR rate. Safety profiles were comparable, with any-grade TRAEs occurring in 53.8% (7/13) of the investigational arm and 46.2% (6/13) of controls, and grade ≥3 TRAEs in 15.4% (2/13) per arm. Diarrhea was predominant in the investigational group, while leukopenia was most frequent in controls. Conclusions: This interim analysis demonstrates that the addition of a sorbitol-supplemented diet to neoadjuvant chemoimmunotherapy significantly enhances therapeutic efficacy in LAGC patients while maintaining a comparable safety profile. Clinical trial information: NCT06826079 .

Persistent infections are notoriously difficult to eradicate, mainly due to biofilm formation and intracellular colonization, which barrier pathogens from antimicrobials, reduce efficacy, and drive recurrence. Infection-induced inflammation further disrupts tissue homeostasis and impairs healing. To address these issues, we designed a multifunctional nanoplatform by one-step self-assembly of Zn2+, tannic acid (TA), and minocycline (MC), yielding biocompatible ZTM nanoparticles (ZTM NPs). Distinct from conventional carriers, this co-assembly strategy enables high drug loading through metal-phenolic coordination, hydrogen bonding, and π-π stacking interactions, thereby integrating MC directly into the dynamic Zn2+-TA network. Notably, the constructed ZTM NPs exhibit dual-responsive properties to the acidic pH and elevated reactive oxygen species (ROS) levels commonly present in infectious microenvironments. Functionally, ZTM NPs effectively disrupt the extracellular polymeric substance (EPS), penetrate the biofilm barrier, and eliminate embedded bacteria. Furthermore, they are capable of crossing the cell membrane barrier, facilitating efficient cellular uptake. Once internalized, the nanoparticles promote lysosomal escape, allowing the delivery of active components into the cytoplasm and contributing to the effective elimination of intracellular bacteria. Beyond antibacterial action, ZTM NPs modulate immunity by scavenging ROS, suppressing NF-κB signaling, and inhibiting M1 macrophage polarization, thereby mitigating inflammation and restoring tissue homeostasis. In vivo, they exhibit potent antibacterial and immunoregulatory efficacy, promoting periodontal regeneration. Overall, ZTM NPs represent a clinically translatable nanoplatform integrating biofilm disruption, intracellular bacterial clearance, and immune modulation.