Abstract Colorectal cancer (CRC) represents one of the most commonly diagnosed malignancies in which Fusobacterium nucleatum (Fn) infiltration critically drives tumor progression by fostering an immunosuppressive tumor microenvironment (TME) that compromises immunotherapy efficacy. Outer membrane vesicles (OMVs) originating from Escherichia coli Nissle 1917 offer an attractive tumor-targeting drug delivery system, combining intrinsic immunostimulatory properties with drug-loading capacity. We therefore developed an OMV-based dual-function system coencapsulating 5-fluorouracil (5-Fu) and metronidazole (MTZ), designated 5-Fu/MTZ@OMVs. In vitro, this system effectively eliminated both CT26 cells and Fn while promoting DC maturation and driving repolarization of M2 macrophages toward M1 as well as N2 neutrophils toward N1. In vivo, upon administration to an Fn-colonized CT26 model, the system homed to tumors, reduced the Fn burden, and inhibited tumor growth, demonstrating its bactericidal and antitumor efficacy. Notably, it reversed immunosuppressive TME by promoting DC maturation, M1 macrophage, and N1 neutrophil polarization, which enhanced the recruitment and functional activation of CD4+ and CD8+ T cells within the tumor. Thus, by integrating bactericidal, antitumor, and immune remodeling activities into a single OMV platform, our strategy constitutes a viable therapeutic approach for Fn-associated CRC.

C 33 H 33 N 3 O 4 , monoclinic, P 2 1 /c (no. 14), a = 10.9636(14) Å, b = 9.6450(12) Å, c = 27.328(4) Å, β = 99.637(2)°, V = 2848.9 Å 3 , Z = 4, R gt ( F ) = 0.0463, wR ref ( F 2 ) = 0.1189, T = 296 K.

The neutrophil-to-lymphocyte ratio (NLR) has emerged as a potential prognostic biomarker in hepatocellular carcinoma (HCC), but its predictive value in patients with unresectable HCC receiving transarterial chemoembolization (TACE) combined with targeted agents and immune checkpoint inhibitors remains unclear. This study aimed to evaluate the prognostic significance of NLR in this setting and to develop individualized nomograms for predicting overall survival (OS) and progression-free survival (PFS). This retrospective real-world cohort consecutively enrolled 148 patients who received TACE combined with molecular targeted agents and immune checkpoint inhibitors between May 2020 and December 2023. OS and PFS were estimated using Kaplan–Meier methods and compared by log-rank test. Prognostic factors were examined using Cox regression. Nomograms incorporating NLR and key clinicopathological variables were constructed, and model performance was assessed using time-dependent area under the curve (AUC) and concordance index (C-index). The cohort was predominantly male (89.9

The precise inhibition of CD47-SIRPα interaction to promote macrophage phagocytosis and thereby mobilize the immune microenvironment is an essential strategy in lung cancer immunotherapy. Herein, we explored the role of Teniposide (Ten/VM-26) in the CD47-SIRPα interactions and macrophage phagocytosis, with insights into the target and molecular mechanism. Ten/VM-26 demonstrated not only chemotherapeutic but also immunostimulatory effects in lung cancer models. Macrophage depletion attenuated the immune activation induced by Ten, which was associated with enhanced phagocytosis, cGAS-STING signaling, and M1 polarization of macrophages. Our data indicated that Ten suppressed CD47 and thereby dampened the interaction between CD47 and SIRPα, which are highly expressed in lung cancer cells and macrophages respectively. Conversely, CD47 supplementation impaired Ten-driven phagocytosis and M1 polarization of macrophages. Further data suggested that Ten bound to TRIM54, which may be involved in CD47 ubiquitination and degradation. To summarize, our findings suggest that Ten down-regulates CD47 through its binding to both CD47 and TRIM54, thereby disrupting the CD47-SIRPα interaction, enhancing macrophage phagocytosis, cGAS-STING activation, and promoting M1 polarization, supporting the potential of targeting CD47 for lung cancer immunotherapy.

Cancer-associated fibroblasts (CAF) account for a high proportion in most solid tumors, including lung cancer, where they exert immunosuppressive function and thereby facilitate cancer progression. Photodynamic therapy (PDT) destroys malignant cells through photo-mediated ROS generation, but its effects on CAF have not been fully explored. The present study aims to investigate these effects and the involved molecular mechanism. The CAF model was established using L929 fibroblasts and Lewis lung cancer cells-derived conditioned medium (LLC CM). Laser-irradiated Chlorin e6 (Ce6) was harnessed to drive PDT. The biomarkers of CAF were detected by Western blotting. Intracellular oxidative stress was analyzed using fluorescence probes and flow cytometry. The dehydrogenase activity (cell viability) of CAF was assessed using the CCK-8 assay. High expression of α-SMA, FAP, and PDGFRβ was identified in the Lewis cell-derived conditioned medium-stimulated CAF. The photosensitizer Ce6 was effectively internalized by CAF without compromising cell dehydrogenase activity under the selected conditions. Further investigation revealed that the screened sublethal Ce6-PDT potentiated a more aggressive phenotype of CAF. Mechanistically, this effect was linked to the reactive oxygen species (ROS) generation and activation of the MAPK signaling pathway driven by oxidative stress. Suppression of oxidative stress and MAPK signaling successfully reversed the aforementioned effect of PDT on CAF activation. Taken together, Ce6-mediated sublethal PDT under specific conditions further promotes CAF activation by oxidative stress and the downstream MAPK signaling pathway, thereby regulating the lung cancer microenvironment. As a study deciphering PDT-mediated regulation of CAF in the tumor immune microenvironment, our work constitutes a pioneering and highly significant exploratory effort.

ABSTRACT The activation and infiltration of cytotoxic T lymphocytes (CTLs) are the key of tumor immunotherapy. However, the suppressive tumor immune microenvironment usually inhibits the function of CTLs. Tumor‐associated macrophages (TAMs) play an important role in remodeling the tumor immune microenvironment. In this work, probiotic Escherichia coli Nissle 1917 (EcN) is used as a bioreactor to achieve intracellular synthesis of copper selenide nanoparticles (Cu 2‐x Se NPs), giving Cu 2‐x Se@EcN, which effectively repolarize macrophages from pro‐tumor M2 phenotype to anti‐tumor M1 phenotype mainly through activating MAPK signaling pathway. The synthesized Cu 2‐x Se NPs exhibited excellent photothermal performance, inducing hyperthermia‐sensitized Fenton‐like reaction to catalyze the generation of hydroxyl radical from H 2 O 2 , then resulted in immunogenic death effect of tumor cells and the repolarization of M2 macrophages. Combined with surface‐expressed pathogen‐associated molecular patterns (PAMPs) of bacteria, Cu 2‐x Se@EcN synergistically promoted DCs maturation and TAMs reprogramming, eventually promoting the infiltration and activation of T cells. Therefore, the bacteria‐inorganic hybrid nanomaterials showed satisfied effect in inhibiting tumor growth and recurrence.

High expression of Lysine-Specific Demethylase 5B (KDM5B) in lung cancer drives tumorigenesis and immunosuppression. KDM5B is negatively correlated with endoplasmic reticulum (ER)-phagy receptors such as TEX264, indicating that selective induction of ER-phagy may degrade KDM5B. Our work revealed that chemotherapeutic drug Teniposide (Ten) was a potent anti-lung cancer agent, which could increase the stability of TEX264. The present study aims to elucidate the critical target and mechanism by which Ten inhibits KDM5B through TEX264-associated ER-phagy against lung cancer. Ten exhibited potent lung cancer suppression ability, as evidenced by the weakened proliferation of organoids and tumor grafts in mice along with activation of the immune microenvironment. Highly-expressed KDM5B demonstrated down-regulation upon Ten treatment, which may be attributed to its degradation via ER-phagy. Blockage of ER-phagy weakened Ten-mediated KDM5B degradation. Insightful investigations discovered that Ten activated OTUD3, a deubiquitylase, which stabilized TEX264, a crucial receptor for ER-phagy. Notably, genetic knockdown of TOP2A impacted little on the Ten-mediated ER-phagy. OTUD3 silencing dampened Ten-driven ER-phagy and KDM5B inhibition. To summarize, these findings demonstrate that Ten effectively inhibits lung cancer and activates immunocytes by KDM5B inhibition, which is regulated by TEX264-associated ER-phagy. Most importantly, OTUD3 serves as an essential target for enhancement of TEX264 stabilization.

The activation and infiltration of cytotoxic T lymphocytes (CTLs) are the key of tumor immunotherapy. However, the suppressive tumor immune microenvironment usually inhibits the function of CTLs. Tumor-associated macrophages (TAMs) play an important role in remodeling the tumor immune microenvironment. In this work, probiotic Escherichia coli Nissle 1917 (EcN) is used as a bioreactor to achieve intracellular synthesis of copper selenide nanoparticles (Cu2-xSe NPs), giving Cu2-xSe@EcN, which effectively repolarize macrophages from pro-tumor M2 phenotype to anti-tumor M1 phenotype mainly through activating MAPK signaling pathway. The synthesized Cu2-xSe NPs exhibited excellent photothermal performance, inducing hyperthermia-sensitized Fenton-like reaction to catalyze the generation of hydroxyl radical from H2O2, then resulted in immunogenic death effect of tumor cells and the repolarization of M2 macrophages. Combined with surface-expressed pathogen-associated molecular patterns (PAMPs) of bacteria, Cu2-xSe@EcN synergistically promoted DCs maturation and TAMs reprogramming, eventually promoting the infiltration and activation of T cells. Therefore, the bacteria-inorganic hybrid nanomaterials showed satisfied effect in inhibiting tumor growth and recurrence.

Non-small cell lung cancer (NSCLC) accounts for the second highest incidence and highest mortality rates globally, wherein immune checkpoint molecules such as PD-L1, highly-expressed in malignant cells bind to PD-1 located in immunocytes, leading to immune escape. We hereby investigate the role of phytomedicine Cepharanthine (CEP) in the regulation of PD-L1 in NSCLC and elucidate the involved mechanism. CEP showed robust cytotoxicity against lung cancer cells, as demonstrated by reduced cell viability and elevated apoptosis. Furthermore, the tumor grafts in mice were significantly suppressed by CEP. Importantly, CEP down-regulated PD-L1 at the mRNA, protein, and membrane levels, thereby arousing the immune microenvironment of lung adenocarcinoma. Further exploration presented that CEP induced autophagy, which specifically accelerated the fusion of lysosomes with autophagosomes, ultimately leading to the degradation of PD-L1 in lung cancer cells. Mechanistically, TSPO and RILP were critical molecules through which CEP accelerated autophagic flux, as validated by drug target techniques and genetic perturbation. Finally, the findings supported the clinical translational potential of CEP plus anti-PD-L1 as a novel chemo-immunotherapy regimen. Taken together, CEP accelerates autophagy through direct inhibition of TSPO and activation of RILP, leading to PD-L1 autophagic degradation, which arouses immune microenvironment of lung adenocarcinoma. The immune regulation effects mediated by CEP prove to be a novel combination chemo-immunotherapy strategy for lung cancer treatment.

Our previous work revealed that cepharanthine (Cep) could elicit endoplasmic reticulum (ER) stress for blocking hepatocellular carcinoma (HCC) development. Nevertheless, the limited distribution of Cep in the ER of HCC restricts its application. In this study, metal organic framework (MOF) modified with N-acetylgalactosamine-rhodamine B and glibenclamide, which was abbreviated as GR-Gli-MOF, were prepared for loading Cep to boost ER stress and anti-HCC immunotherapy. The morphology, particle size, zeta potential, elemental composition, characteristic Ultraviolet–Visible absorption, and infrared vibration peaks were identified, verifying the successful preparation of Cep@GR-Gli-MOF. Further fluorescence imaging and sections results showed the prominent distribution of Cep@GR-Gli-MOF in tumor tissues. Cep@GR-Gli-MOF exhibited potent targeting in HCC cells and the ER, which released Cep and iron ions under acid conditions and triggered robust ER stress for facilitating Calreticulin (CRT) membrane translocation and immunogenic cell death. Significant efficacy was observed in subcutaneous and in situ HCC-bearing mice treated with Cep@GR-Gli-MOF, superior to free Cep and other agents. To summarize, the prepared Cep-loaded MOF possesses characterization of cascade targeting to the ER of HCC. Cep@GR-Gli-MOF induce vigorous ER stress and boost immunotherapy against HCC. The present work provides novel insight for how natural phytomedicine synergize with chemical vectors to mediate cancer immunotherapy.

Teniposide (Ten/VM-26) is low in toxicity and has proven to be effective in destroying malignant cells at low doses. However, the target and molecular mechanism of Ten/VM-26 are poorly understood, which limits its clinical application against solid malignant cancers. Apurinic/apyrimidinic endonuclease 1 (APEX1) expression is upregulated in lung cancer, which could effectively suppress DNA damage. The present study aims to explore how Ten/VM-26 regulates APEX1 and thereby exploits its antilung cancer effects. Ten/VM-26 possessed powerful antilung cancer efficacy in vitro and organoid models. Furthermore, the findings of in vivo experiments evidenced that Ten/VM-26 could suppress the growth of tumor grafts without impacting the vital organs or body weight of mice. RNA-sequence analysis revealed that Ten/VM-26 treatment led to differentially expressed genes (DEGs), which were enriched in the DNA damage-associated biological process (BP). Reactive oxygen species (ROS) generation mediated by Ten/VM-26 was the major contributor to its anticancer effect. The in-depth investigation identified that APEX1 was efficiently expressed in lung cancer tissues, leading to a poor prognosis. Interestingly, APEX1 was downregulated in the presence of Ten/VM-26, which further abolished the protection of DNA, resulting in robust DNA damage. Further findings discovered that Ten/VM-26 could bind to APEX1 and thereby dampen its function. In contrast, APEX1 recovery attenuated the Ten/VM-26-induced DNA damage and anticancer efficacy. In summary, these data make a strong argument for the notion that Ten/VM-26-mediated inhibition of APEX1 contributes to DNA damage and thereby achieves favorable antilung cancer effects, wherein Ten/VM-26 could down-regulate APEX1 by binding and ubiquitination. The current study presents a critical target and mechanism for Ten/VM-26-mediated antilung cancer therapy.

Immunoradiotherapy (iRT) has emerged as a promising strategy for liver hepatocellular carcinoma (LIHC) treatment to synergistically activate both localized antitumor immunity and systemic immune responses. However, radiation will aggravate LIHC hypoxia, resulting in an adenosine metabolism level elevation, which promotes the differentiation of T cells into terminally exhausted phenotypes and weakens the efficacy of immunotherapy. To overcome this challenge, we engineered a nanocatalytic probiotic-based radiation-metabolic modulator, in which Escherichia coli Nissle 1917 (EcN) was programmed to in situ synthesize gold-palladium bimetallic nanocatalysts (EcNcGP) via biodirected mineralization. Guided by lattice mismatch and interfacial strain engineering, engineered EcN orchestrates the epitaxial assembly of Au atoms on Pd nanoclusters, yielding a precisely strain-tuned heterostructure with a modulated d-band electronic structure. This architectural design optimizes oxygen intermediate adsorption-desorption kinetics and significantly enhances the catalytic efficiency. This design enables EcNcGP to exhibit robust catalase- and peroxidase-like activities, which effectively catalyze intratumoral H2O2 into O2 and hydroxyl radicals, intensifying radiation damage and alleviating tumor hypoxia to inhibit adenosine metabolism by downregulating the expression of ectonucleoside triphosphate diphosphate hydrolase 1 (CD39) and ecto-5'-nucleotidase (CD73). By blocking the binding of adenosine (ADO)-adenosine receptor A2A (ADORA2A) to inhibit the following cyclic adenosine monophosphate (cAMP)-protein kinase A (PKA)-phosphorylation of cAMP response element binding (pCREB) signaling transduction, radiation-induced T-cell exhaustion could be inhibited. Compared to stereotactic body radiotherapy (SBRT), the combination of EcNcGP with SBRT increased CD8+ T-cell infiltration by 99.8% and reduced PD-1hi-exhausted T cells by 63.9%. Integration with anti-PD-L1 therapy (αPD-L1) achieved complete tumor regression in 60% of the treated mice-bearing orthotopic hepatocellular carcinoma. These findings establish a paradigm-shifting strategy for reprogramming tumor-immune metabolic checkpoints using strain-engineered nanocatalytic probiotics, thereby enhancing iRT and overcoming radioresistance.

Harringtonine (HT) is an alkaloid extracted from the botanical cephalotaxus fortunei Hook.f., which has potent anti-tumor activity. Nevertheless, the target and mechanism of HT in cancer have not been reported. The present work aims to explore the crucial target of HT in triggering ferroptosis and elucidate its mechanism. Lewis lung cancer cells and tumor-bearing mice models prepared thereof were used in this study. Network pharmacology and RNA sequencing were utilized to screen the pivotal target and information. Flow cytometry, Western blots, qRT-PCR, and immunoprecipitation were exploited to elucidate the mechanism. The affinity experiments were employed to analyze the interaction of HT and FASN. Reduced cell viability and increased apoptosis were observed in HT-treated lung cancer cells and the 3-D cell model. Consistently, HT exhibited pronounced anti-cancer effects in in vivo experiments. The interaction molecules of HT and lung cancer were enriched in ferroptosis, which was validated by the accumulation of ferrous ions etc. Blockage of ferroptosis mitigated HT-mediated efficacy. Further investigation showed alternations in fatty acid metabolism when adding HT, especially fatty acid synthase (FASN). HT was demonstrated to bind to FASN, thereby dampening SYVN1-mediated ubiquitination. Finally, the silence of FASN dampened the ferroptosis and anti-cancer efficacy introduced by HT. Collectively, HT could bind to FASN and thereby enhance the activity by reducing ubiquitination, resulting in increased fatty acid synthesis and infiltrating into the membrane, which leads to ferroptosis. The present work identifies the critical target for phytomedicine HT-driven ferroptosis and provides a foundation for cancer therapy.

Pyroptosis is the critical approach for the induction of robust cancer cell death and activation of the immune microenvironment, which often results from mitochondrial damage. Herein, a combination strategy of sonodynamic-chemotherapy is designed to achieve an anti-heptocellular (HCC) effect, wherein the cepharanthine (Cep), a kind of functional phytomedicine, is loaded into the Tris(chlorisopropyl)Phosphate (TCPP) Metal-organic framework (MOF). The Cep@TCPP-MOF is successfully developed, as characterized by techniques such as transmission electron microscopy (TEM) and dynamic light scattering (DLC). The tumor-targeted ability of Cep@TCPP-MOF is validated by in vivo imaging. In-depth in vitro experiments presented Cep@TCPP-MOF can be taken up by Huh-7 and HepG2 cells, which collapse in response to the sonodynamic therapy (SDT). The released Cep can bind to an inactive translocator protein (TSPO), a kind of transporter on the membrane of mitochondria, while TCPP induces ROS generation under the SDT, thereby enhancing mitochondria damage. Further exploration shows that the Cep@TCPP-MOF treatment induces pronounced pyroptosis, which leads to HCC inhibition. To sum up, sonodynamic-chemotherapy nanoplatforms, composed by Cep-loaded TCPP-MOF are developed, which have sonodynamic responsiveness to release Cep and TCPP. TSPO inhibition-induced mitochondrial damage by Cep, coupled with ROS generated by TCPP-SDT, synergistically elicits pyroptosis and thereby fulfills the anti-HCC role.

Sorafenib (Sor), a multi-kinase inhibitor, serves as the first-line systemic therapeutic drug for advanced hepatocellular carcinoma (HCC). Unfortunately, clinical benefit was confirmed in only a minority of patients, limiting clinical application of Sor. Using nanotechnology to enhance the therapeutic effect of anti-cancer drugs has become a major trend. Accordingly, a Fe(III)-based metal-organic framework (MOF) nanocarrier encapsulating Sor (Sor@Fe-MOF) with ferroptosis/immune activation functions was constructed for HCC therapy. In vivo and in vitro assays demonstrated that these prepared Sor@Fe-MOF nanoparticles (NPs) exhibited favorable therapeutic activities against HCC, characterized by increasing ferroptosis and remodeling tumor immune microenvironment. Compared with free Sor, Sor@Fe-MOF produced the additive effects that induce ferroptotic cell death in HCC cells through downregulating GPX4 and SLC7A11 and upregulating ACSL4. Using orthotopic tumor mouse model and humanized PBMC mouse model, we also found that Sor@Fe-MOF obviously activated the anti-HCC immunity via increasing tumor infiltration of CD8+ T cells. Upon internalization by CD8+ T lymphocytes, Sor@Fe-MOF effectively facilitated the activation and tumor penetration of these immune cells. No obvious morphological changes of mice organs implied the distinctive biological security during Sor@Fe-MOF treatment. Taken together, our findings highlighted the excellent capacity of Sor@Fe-MOF to facilitate ferroptosis and remodel immune microenvironment, consequentially improving therapeutic response of Sor. These prepared Sor@Fe-MOF NPs could be function as a promising alternative strategy for HCC treatment.

Phase separation, particularly liquid-liquid phase separation (LLPS), has emerged as a powerful tool in biological research, offering unique advantages for visualizing and analyzing biomolecular interactions. This review highlights recent advances in leveraging LLPS to develop experimental techniques for studying protein-protein interactions (PPIs), protein-RNA interactions, and enzyme activity. The integration of LLPS with advanced techniques has expanded its applications, offering new possibilities for unraveling the complexities of cellular function and disease mechanisms. Looking forward, the development of more versatile, sensitive, and targeted LLPS-based methods is poised to transform molecular biology, providing deeper insights into cellular dynamics and facilitating therapeutic advancements.

Ganoderma acid A (GAA), a triterpenoid compound from Ganoderma lucidum, has gained attention for its anti-tumor properties. Herein, we hypothesized that GAA may enhance cisplatin’s (DDP) anticancer effect in gallbladder cancer (GBC) cells by promoting DNA damage response, particularly through upregulation of DNA damage markers such as γH2AX, p-ATM, p-ATR, and p-p53, and reducing cell stemness by downregulating stemness markers like SOX2, Oct4, and NANOG. The human GBC cell line GBC-SD and human gallbladder epithelial cell line HGBEC were cultured in RPMI-1640 and DMEM/F12 media with 10

Calcium overload is a promising anticancer treatment that kills tumor cells primarily by causing mitochondrial dysfunction in cells. However, calcium overload therapy is limited by inefficient cellular uptake of Ca 2+ . Herein, a triboelectric immunotherapy/calcium electroporation (CaEP) synergistic tumor therapy is developed using electrostatic‐breakdown induced direct‐current (DC) generated by a triboelectric nanogenerator (TENG). In this work, an 8 × 10 cm TENG can generate approximately 5–30 pulsed DC with a peak output of 60 µA in a single sliding. The pulsed DC can not only directly damage tumor cells and activate T cells‐mediated adaptive immunity response to inhibit tumor growth (that is, triboelectric immunotherapy), but also promote the cellular uptake of Ca 2+ (increased up to 235.9% in vitro) by electroporation to improve the therapeutic effect of calcium overload tumor therapy. The triboelectric immunotherapy/CaEP treatment can increase IL‐12 and TNF‐α within the tumor tissue to 175.7% and 185.5%, respectively, illustrating the upregulation of immune‐promoting factor levels. Moreover, the adenosine triphosphate (ATP) leakage and high mobility group box 1 protein (HMGB1) release are also enhanced (increased to 211.2%, and 154.3%, respectively). This work offers an effective electrical‐assisted tumor therapy technique and provides proof of concept of this technique as a miniaturized tumor treatment system for solid tumors.

The dysregulated macrophage phenotype, as the main cause of colitis, not only enhanced oxidative stress to exacerbate inflammatory responses but was closely related with gut microbial dysbiosis. It was needed to simultaneously address the three issues for the effective treatment of colitis, but it was not satisfied. Here, we developed "three-birds-one-stone" probiotics, named Se@EcN-C2/A2, for colitis treatment. Escherichia coli Nissle 1917 (EcN), a clinically approved probiotic, was used to intracellularly synthesize selenium (Se) nanoparticles by biomineralization, giving Se@EcN. Coating glycol chitosan and sodium alginate on the surface of Se@EcN (Se@EcN-C2/A2) endowed probiotics with high resistance to the harsh gastrointestinal tract environment and strong adhesion and targeting ability to the inflamed site of the colon to facilitate the uptake by M1 macrophages. Se@EcN-C2/A2 was metabolized to SeCys2 and MetSeCys to be involved in the synthesis of GPX2 and TXNRD1, which led to reaction oxygen species clearance to inhibit Toll-like receptor and nuclear factor κB signaling pathways to suppress inflammatory response and polarize M1 macrophages to M2 phenotypes by activating PI3K/AKT signaling pathways. In DSS-induced colitis mice, Se@EcN-C2/A2 exerted satisfactory therapeutic and prophylactic effects, including scavenging oxidative stress and regulating macrophage phenotypes to suppress inflammatory response and restore gut barrier functions. Moreover, the living probiotic EcN in the colon effectively regulated microbial dysbiosis by decreasing the abundance of Escherichia-Shigella and increasing the abundance of Lactobacillus and Bifidobacterium.

Implantable controlled local drug delivery offers many advantages over systemic delivery. However, wirelessly controlling drug release from implanted devices via exogenous stimulation remains challenging. Herein, an ultrasound wirelessly controlled electrically responsive implantable drug delivery system (UI-TENG-IDDS) is proposed, which consists of an ultrasound-driven implantable triboelectric nanogenerator (UI-TENG) and an electrically responsive drug reservoir. When ultrasound is applied to the skin, it induces high-frequency vibrations in the UI-TENG, generating pulsed electrical output (≈50 µA at 9 V) to electrolyze water, thereby increasing the alkalinity near the cathode and dissolving drug carrier (co-PMMA) to release drugs. Moreover, UI-TENG-IDDS can accelerate the diffusion of negatively charged drugs via iontophoresis mechanism. Methotrexate (MTX) loaded UI-TENG-IDDS has been applied to ablate tumors without causing evident side effects. The UI-TENG-IDDS can wirelessly control drug release without complex electronic design and the electrical outputs are not limited by the battery life and capacity, avoiding battery replacement surgery. Considering the advantage that TENG can be fabricated using biodegradable and biocompatible materials, this work provides an efficient, economical, and safe regimen for spatiotemporal controlled implantable drug delivery.