Bacterial Biohybrids for Invasion of Tumor Cells Promote Antigen Cross-Presentation Through Gap Junction.

Due to inherent differences in cellular composition and metabolic behavior with host cells, tumor-harbored bacteria can discriminatorily affect tumor immune landscape. However, the mechanisms by which intracellular bacteria affect antigen presentation process between tumor cells and antigen-presenting cells (APCs) are largely unknown. The invasion behavior of attenuated Salmonella VNP20009 (VNP) into tumor cells is investigated and an attempt is made to modulate this behavior by modifying positively charged polymers on the surface of VNP. It is found that non-toxic chitosan oligosaccharide (COS) modified VNP (VNP@COS) bolsters the formation of gap junction between tumor cells and APCs by enhancing the ability of VNP to infect tumor cells. On this basis, a bacterial biohybrid is designed to promote in situ antigen cross-presentation through intracellular bacteria induced gap junction. This bacterial biohybrid also enhances the expression of major histocompatibility complex class I molecules on the surface of tumor cells through the incorporation of Mdivi-1 coupled with VNP@COS. This strategic integration serves to heighten the immunogenic exposure of tumor antigens; while, preserving the cytotoxic potency of T cells. A strategy is proposed to precisely controlling the function and local effects of microorganisms within tumors.

Self-Assembled Copper-Based Nanoparticles for Glutathione Activated and Enzymatic Cascade-Enhanced Ferroptosis and Immunotherapy in Cancer Treatment.

As an emerging cancer treatment strategy, ferroptosis is greatly restricted by excessive glutathione (GSH) in tumor microenvironment (TME) and low reactive oxygen species (ROS) generation efficiency. Here, this work designs self-assembled copper-alanine nanoparticles (CACG) loaded with glucose oxidase (GOx) and cinnamaldehyde (Cin) for in situ glutathione activated and enzymatic cascade-enhanced ferroptosis and immunotherapy. In response to GSH-rich and acidic TME, CACG allows to effectively co-deliver Cu2+ , Cin, and GOx into tumors. Released Cin consumes GSH through Michael addition, accompanying with the reduction of Cu2+ into Cu+ for further GSH depletion. With the cascade of Cu+ -catalyzed Fenton reactions and enzyme-catalyzed reactions by GOx, CACG could get rid of the restriction of insufficient hydrogen peroxide in TME, leading to a robust and constant generation of ROS. With the high efficiency of GSH depletion and ROS production, ferroptosis is significantly enhanced by CACG in vivo. Moreover, elevated oxidative stress triggers robust immune responses by promoting dendritic cells maturation and T cell infiltration. The in vivo results prove that CACG could efficiently inhibit tumor growth in 4T1 tumor-bearing mouse model without causing obvious systemic toxicity, suggesting the great potential of CACG in enhancing ferroptosis and immunotherapy for effective cancer treatment.

Targeting to Tumor-Harbored Bacteria for Precision Tumor Therapy.

The differential tumor environment guides various antitumor drug delivery strategies for efficient cancer treatment. Here, based on the special bacteria-enriched tumor environment, we report a different drug delivery strategy by targeting bacteria inhabiting tumor sites. With a tissue microarray analysis, it was found that bacteria amounts displayed significant differences between tumor and normal tissues. Bacteria-targeted mesoporous silica nanoparticles decorated with bacterial lipoteichoic acid (LTA) antibody (LTA-MSNs) could precisely target bacteria in tumors and deliver antitumor drugs. By the intravenous administration of bacteria-targeted nanoparticles, we showed in mice with colon cancer, lung cancer, and breast cancer that LTA-MSNs exhibited a high tumor-targeting ability. As a proof-of-concept study, tumor microbes as some of the characteristics of a tumor environment could be utilized as potential targets for tumor targeting. This bacteria-guided tumor-targeting strategy might have great potential in differential drug delivery and cancer treatment.

Interference of Glucose Bioavailability of Tumor by Engineered Biohybrids for Potentiating Targeting and Uptake of Antitumor Nanodrugs.

The chemotherapy efficacy of nanodrugs is restricted by poor tumor targeting and uptake. Here, an engineered biohybrid living material (designated as EcN@HPB) is constructed by integrating paclitaxel and BAY-876 bound human serum albumin nanodrugs (HPB) with Escherichia coli Nissle 1917 (EcN). Due to the inherent tumor tropism of EcN, EcN@HPB could actively target the tumor site and competitively deprive glucose through bacterial respiration. Thus, albumin would be used as an alternative nutrient source for tumor metabolism, which significantly promotes the internalization of HPB by tumor cells. Subsequently, BAY-876 internalized along with HPB nanodrugs would further depress glucose uptake of tumor cells via inhibiting glucose transporter 1 (GLUT1). Together, the decline of glucose bioavailability of tumor cells would activate and promote the macropinocytosis in an AMP-activated protein kinase (AMPK)-dependent manner, resulting in more uptake of HPB by tumor cells and boosting the therapeutic outcome of paclitaxel.

Biomaterial-mediated modulation of oral microbiota synergizes with PD-1 blockade in mice with oral squamous cell carcinoma.

Because a host's immune system is affected by host-microbiota interactions, means of modulating the microbiota could be leveraged to augment the effectiveness of cancer therapies. Here we report that patients with oral squamous cell carcinoma (OSCC) whose tumours contained higher levels of bacteria of the genus Peptostreptococcus had higher probability of long-term survival. We then show that in mice with murine OSCC tumours injected with oral microbiota from patients with OSCCs, antitumour responses were enhanced by the subcutaneous delivery of an adhesive hydrogel incorporating silver nanoparticles (which inhibited the growth of bacteria competing with Peptostreptococcus) alongside the intratumoural delivery of the bacterium P. anaerobius (which upregulated the levels of Peptostreptococcus). We also show that in mice with subcutaneous or orthotopic murine OSCC tumours, combination therapy with the two components (nanoparticle-incorporating hydrogel and exogenous P. anaerobius) synergized with checkpoint inhibition with programmed death-1. Our findings suggest that biomaterials can be designed to modulate human microbiota to augment antitumour immune responses.

A Self-Driven Bioreactor Based on Bacterium-Metal-Organic Framework Biohybrids for Boosting Chemotherapy via Cyclic Lactate Catabolism.

The excessive lactate in the tumor microenvironment always leads to poor therapeutic outcomes of chemotherapy. In this study, a self-driven bioreactor (defined as SO@MDH, where SO is Shewanella oneidensis MR-1 and MDH is MIL-101 metal-organic framework nanoparticles/doxorubicin/hyaluronic acid) is rationally constructed via the integration of doxorubicin (DOX)-loaded metal-organic framework (MOF) MIL-101 nanoparticles with SO to sensitize chemotherapy. Owing to the intrinsic tumor tropism and electron-driven respiration of SO, the biohybrid SO@MDH could actively target and colonize hypoxic and eutrophic tumor regions and anaerobically metabolize lactate accompanied by the transfer of electrons to Fe3+, which is the key component of the MIL-101 nanoparticles. As a result, the intratumoral lactate would undergo continuous catabolism coupled with the reduction of Fe3+ to Fe2+ and the subsequent degradation of MIL-101 frameworks, leading to an expeditious drug release for effective chemotherapy. Meanwhile, the generated Fe2+ will be promptly oxidized by the abundant hydrogen peroxide in the tumor microenvironment to reproduce Fe3+, which is, in turn, beneficial to circularly catabolize lactate and boost chemotherapy. More importantly, the consumption of intratumoral lactic acid could significantly inhibit the expression of multidrug resistance-related ABCB1 protein (also named P-glycoprotein (P-gp)) for conquering drug-resistant tumors. SO@MDH demonstrated here holds high tumor specificity and promising chemotherapeutic efficacy for suppressing tumor growth and overcoming multidrug resistance, confirming its potential prospects in cancer therapy.

An RGB-emitting molecular cocktail for the detection of bacterial fingerprints.

Accumulating evidence indicates that colonized microbes play a crucial role in regulating health and disease in the human body. Detecting microbes should be essential for understanding the relationship between microbes and diseases, as well as increasing our ability to detect diseases. Here, a combined metabolic labeling strategy was developed to identify different bacterial species and microbiota by the use of three different fluorescent metabolite derivatives emitting red, green, and blue (RGB) fluorescence. Upon co-incubation with microbes, these fluorescent metabolite derivatives are incorporated into bacteria, generating unique true-color fingerprints for different bacterial species and different microbiota. A portable spectrometer was also fabricated to automate the colorimetric analysis in combination with a smartphone to conveniently identify different bacterial species and microbiota. Herein, the effectiveness of this system was demonstrated by the identification of certain bacterial species and microbiota in mice with different diseases, such as skin infections and bacteremia. By analyzing the microbiota fingerprints of saliva samples from clinical patients and healthy people, this system was proved to precisely distinguish oral squamous cell carcinoma (OSCC, n = 29) samples from precancerous (n = 10) and healthy (n = 5) samples.

Controllable gelation of artificial extracellular matrix for altering mass transport and improving cancer therapies.

Global alterations in the metabolic network provide substances and energy to support tumor progression. To fuel these metabolic processes, extracellular matrix (ECM) plays a dominant role in supporting the mass transport and providing essential nutrients. Here, we report a fibrinogen and thrombin based coagulation system to construct an artificial ECM (aECM) for selectively cutting-off the tumor metabolic flux. Once a micro-wound is induced, a cascaded gelation of aECM can be triggered to besiege the tumor. Studies on cell behaviors and metabolomics reveal that aECM cuts off the mass transport and leads to a tumor specific starvation to inhibit tumor growth. In orthotopic and spontaneous murine tumor models, this physical barrier also hinders cancer cells from distant metastasis. The in vivo gelation provides an efficient approach to selectively alter the tumor mass transport. This strategy results in a 77% suppression of tumor growth. Most importantly, the gelation of aECM can be induced by clinical operations such as ultrasonic treatment, surgery or radiotherapy, implying this strategy is potential to be translated into a clinical combination regimen.

A star-shaped molecularly imprinted polymer derived from polyhedral oligomeric silsesquioxanes with improved site accessibility and capacity for enantiomeric separation via capillary electrochromatography.

A star-shaped molecularly imprinted coating was prepared starting from octavinyl-modified polyhedral oligomeric silsesquioxanes (Ov-POSS). It possesses a relatively open structure and has good site accessibility and a larger capacity even at lower cross-linking. The imprinted coating was prepared from S-amlodipine (S-AML) as the template and analyte, Ov-POSS as the cross-linker, and methacrylic acid as the functional monomer. The preparation and chromatographic parameters were optimized, including ratio of template to functional monomer, apparent cross-linking degree, pH value, ACN content and salt concentration in the mobile phase. The best resolution in enantiomer separation by means of capillary electrochromatography reaches a value of 33. A good recognition ability (α = 2.60) was obtained and the column efficiency for S-AML was 54,000 plates m-1. The use of Ov-POSS as a cross-linker significantly improves the column capacity and thus the detection sensitivity. The results show that Ov-POSS is an effective cross-linker for the preparation of imprinted polymers with good accessibility and large capacity. Graphical abstract Schematic presentation of the preparation of star-shaped imprinted polymer using octavinyl-modified polyhedral oligomeric silsesquioxanes (Ov-POSS) and by using methacrylic acid (MAA) as functional monomer. The best enantiometric resolution (33) for amlodipine (AML) can be achieved in capillary chromatography (CEC).