Polymerization of L-Arginine into Nanomicelles for Immunometabolic Engineering of Adoptive Macrophages in Solid Tumor Therapy.

The therapeutic efficacy of adoptive cell therapy is highly dependent on the status and function of the infused cells. However, insufficient nutrient availability within the immunosuppressive tumor microenvironment (TME) often impedes these cells from fully exerting their cytotoxic potential against solid tumors. Here, we present a strategy of integrating adoptively transferred macrophages with intracellular nutrient depots composed of L-arginine-based nanomicelles to provide a sustainable supply of essential metabolite and optimize the cellular activity in the nutrient-deprived TME.

Proteolysis-triggered RNA Interference for Mitochondrial Iron Dyshomeostasis to Activate Antitumor Immunity in Hepatic Carcinoma.

Although the disturbance of iron metabolism holds significant promise for antitumor therapy, the specific regulation of the precise acting site remains challenging. Here, a self-triggering proteolysis RNA interference system (cRGD-VFs) is elaborately constructed to precisely disturb mitochondrial iron homeostasis, the core hub of cellular iron regulation, for evoking antitumor immunity. Specifically, ferritin is conjugated with E3 ligase ligand VH032 and tumor-targeting cRGD peptide through click chemistry, and further loaded with ENO1-targeted siRNA to prepare cRGD-VFs.

Gamma Oscillation Disruption Induced By Microglial Activation Contributes to Perioperative Neurocognitive Disorders in Aged Mice.

Perioperative neurocognitive disorder (PND) is a prevalent postoperative complication of the central nervous system (CNS) in elderly patients. Advanced age is an independent risk factor for developing PND. Microglia are essential immune cells in the CNS and play a critical role in neuroinflammation.

VaccineIntegrated Nanoplatform for Lactate-Activatable Chemo/Chemodynamic Therapy and Multiple Immune Regulations of Tumor.

Enhancing the synergistic effect of chemo-immunotherapy remains a major challenge in the field of cancer treatment. Besides, the premature release of chemotherapeutic or immunotherapeutic agents usually causes systemic immune disorders, leading to the weakness of immunotherapy. Here, a vaccine-integrated hollow MnO nanoplatform (TMLV), co-loaded with tirapazamine (TPZ) and lactate oxidase (LOX), is developed to orchestrate lactate-activatable multiple immune regulations against tumor.

Lactate-Fueled Bacteria Generator for Bioelectricity-Responsive Release of Antitumor Drug.

In the current landscape of precision medicine, the innovation of stimulus-responsive drug delivery systems stands at the forefront of advancing targeted cancer therapies. Electrically responsive drug delivery systems show considerable application potential, but their reliance on external power sources makes it difficult for drugs to reach deep-seated tumor sites. Moreover, the issue of drug resistance during chemotherapy severely limits therapeutic efficacy.

Biomineralized Engineered Bacterial Outer Membrane Vesicles as cGAS-STING Nanoagonists Synergize with Lactate Metabolism Modulation to Potentiate Immunotherapy.

The immunosuppressive tumor microenvironment (TME) significantly limits the efficacy of cancer immunotherapy. Activation of the cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS) stimulator of interferon genes (STING) pathway and depletion of the tumor metabolic byproduct lactate (LA) represent promising strategies to reverse the immunosuppressive TME and enhance antitumor therapeutic outcomes. Herein, biomineralized engineered bacterial outer membrane vesicles (OMVs@MnCaP-FA) are developed to synergistically activate the cGAS-STING pathway and modulate LA metabolism for antitumor immunotherapy.

Directly Evolved Nanovaccines Modulate Disrupted Circadian Rhythm and Enhance Cancer Immunotherapy.

The circadian rhythm, as a crucial endogenous biological oscillator, often undergoes disruptions, thus fostering severe immunosuppression within tumors. Here, this work develops directly evolved biovesicles as biological clock-modulated nanovaccines (Clock-NVs) to augment circadian clock gene expression and enhance cancer immunotherapy. These biovesicles act as bioreactors, transforming an unfavorable factor, ROS, into a beneficial circadian clock enhancer, oxygen.

Functional Delivery Systems for Targeting Tumor Heterogeneity: Reversing Immunosuppression and Modulating Cancer-Immune Interplay.

Understanding and modulating the interplay between cancer cells and immune cells is critical for deciphering cancer progression and developing effective therapies. However, studying this interplay using patient-derived cells in animal models remains challenging, and the inherent heterogeneity of human tumors adds complexity to traditional approaches. Here, we demonstrate that functional delivery systems targeting heterogeneous malignant cells enable precise immune modulation and real-time assessment of cancer-immune interactions.

Engineering hypoxia-specific core-shell nanotherapeutics: A sequential strategy for amplified multimodal synergistic breast cancer treatment.

The reactive oxygen species (ROS)-based chemodynamic therapy (CDT) and sonodynamic therapy (SDT) have garnered significant interests in advanced tumor treatments. However, their therapeutic efficacy is severely hindered by tumor hypoxia and overexpressed antioxidant glutathione (GSH) in the tumor microenvironment (TME). Motivated by the concept of metal coordination-based nanomedicine, we proposed an innovative strategy for synergistic tumor therapy tailored to the TME.

Oleanolic acid derivative OA17 inhibits trophoblast apoptosis by suppressing HIF-1α nuclear translocation in SLE-associated adverse pregnancy outcomes.

Background: Systemic lupus erythematosus (SLE) primarily affects women of reproductive age and is associated with a high incidence of adverse pregnancy outcomes (APOs). Recent studies reveal that elevated HIF-1α expression in the placenta is involved in SLE-associated APOs and multiple pregnancy complications, but no clinically approved HIF-1α inhibitors exist to mitigate APOs. OA17, a pentacyclic triterpenoid derived from structural modification of oleanolic acid (OA), exhibits potent anti-inflammatory and antioxidant properties.

Antibacterial Peptides-Produced Cell Hydrogel Eliminates Intracellular Pathogens and Remodels Immune Microenvironment for Osteomyelitis Therapy.

Featuring bacterial invasion and colonization within cells, chronic infection-induced immune suppression, and inflammatory cell infiltration, osteomyelitis is currently an intractable and recurrent bone disease. In this study, an injectable hydrogel that gels in situ and is loaded with engineered antimicrobial cells (LL37-MSC@OCAHM) is developed. This anti-inflammatory hydrogel not only maintains cell activity in the inflammatory environment but also releases magnesium ions (Mg) to promote the differentiation of MSCs into bone-forming cells, contributing to bone mass formation, enhancing bone repair, and accelerating bone healing.

Layer-by-Layer Deposition of Antigen Peptides on Bifidobacterium for Subintestinal Lymphatic System-Guided Personalized Tumor Immunotherapy.

Gut-associated lymphoid tissue (GALT) possesses a highly specialized immune system and is rational as a foothold for oral tumor vaccines. Here, a noninvasive oral vaccine (Bif-OVA-Ocur) is designed to engage GALT, inducing both intestinal mucosal and systemic immunity for tumor therapeutics. The vaccine uses Bifidobacterium (Bif) as a delivery vehicle for tumor antigen peptides, which are coated with antigen peptides (OVA) and oxidized curdlan (Ocur) in a layer-by-layer (LBL) manner.

Click Chemistry-Assisted Rejuvenation of Aging T Cells Sensitizes Aged Mice to Tumor Immunotherapy.

Enormous resources have been devoted to address the suboptimal response of tumor patients to immunotherapy. However, a crucial yet often overlooked factor in these effects is the strong correlation between the occurrence and development of tumors and the immune dysfunction associated with aging. Our study aims to rejuvenate aging T cells within tumor-draining lymph nodes (TdLNs) by using targeted delivery of rapamycin, a macrolide capable of mitigating aging-related decline in immune function, thereby enhancing the antitumor efficacy of immunotherapy in aged mice.

An orally administered gene editing nanoparticle boosts chemo-immunotherapy in colorectal cancer.

Chemoresistance and immunosuppression are common obstacles to the efficacy of chemo-immunotherapy in colorectal cancer (CRC) and are regulated by mitochondrial chaperone proteins. Here we show that the disruption of the tumour necrosis factor receptor-associated protein 1 (TRAP1) gene, which encodes a mitochondrial chaperone in tumour cells, causes the translocation of cyclophilin D in tumour cells. This process results in the continuous opening of the mitochondrial permeability transition pore, which enhances chemotherapy-induced cell necrosis and promotes immune responses.

Targeted tumor therapy with L-cyst(e)ine-addicted bacteria-nanodrug biohybrids.

Bacteria-based metabolic therapy has been acknowledged as a promising strategy for tumor treatment. However, the insufficient efficiency of wild-type bacteria severely restricts their therapeutic efficacy. Here, we elaborately develop an ʟ-cyst(e)ine-addicted bacteria-nanodrug biohybrid for metabolic therapy through a dual-selection directed evolution strategy.

HIF-1α mediates mitochondrial damage by down-regulating ALKBH7 expression to promote the aberrant activation of FLS in rheumatoid arthritis.

Rheumatoid arthritis (RA) is an autoimmune disease characterized by synovial inflammation and progressive joint destruction. Existing evidence indicates that hypoxia potentially contributes to the pathology of RA, though the specific mechanism remains unidentified. In this study, we explored the molecular mechanism through which the hypoxia-inducible factor (HIF-1α) contributed to the pathological process of RA.

Molecular detection of Bartonella in bats and their ectoparasites, Spinturnix myoti, from central and Western Yunnan Province, China.

Bartonella, a facultative intracellular pathogen, is known for causing zoonotic diseases and has been detected in a variety of mammals and arthropods. Previous research has highlighted bats as natural reservoirs for Bartonella, with bat ectoparasites acting as vectors for transmission. Moreover, studies have indicated a positive correlation between the prevalence of ectoparasites and Bartonella infection levels.

Injectable multifunctional hydrogels for adipose tissue remodeling to treat obesity and alleviate metabolic syndrome.

Dysfunction of adipose tissue in obese individuals is associated with metabolic imbalances. Current treatments focus on reducing calorie intake and increasing exercise but have unsatisfactory efficacy and significant side effects. Here, a subcutaneously in situ formed therapeutic hydrogel (RL lip@gel) that can simultaneously modulate the inflammatory environment of adipose tissue and induce adipocyte browning is developed to combat obesity.

Acid-Responsive Biocompatible Hydrogel Modulating Tumor DNA Self-Repair Collaborated with Chemotherapy for Boosting STING Pathway-Associated Immunotherapy.

In this study, an acid-responsive hydrogel (ODCM@AZD) encapsulating doxorubicin (DOX), Mn, and AZD2281 is rationally engineered for synergistic chemo-immunotherapy. Notably, ODCM@AZD can be specifically degraded within the tumor microenvironment to release the loaded therapeutic agents. Specifically, the released DOX kills tumor cells to produce abundant cytoplasmic DNA, while the freed AZD2281 inhibits the DNA repair pathway of tumor cells to enhance the chemotherapeutic effect and promote the accumulation of damaged DNA, which is further aggravated by reactive oxygen species (ROS) generated from the Mn-mediated Fenton-like reaction.

MnO-Assisted Photosynthetic Bacteria Interfering with the Adenosine-A2AR Metabolic Pathway to Enhance Tumor Photothermal Immunotherapy.

Hypoxia-related adenosine (Ado) exerts an immunosuppressive effect in tumors by binding to the metabolic checkpoint Ado A2A receptors (A2AR), thereby hindering the activation of antitumor immunity induced by immunogenic cell death (ICD). In this study, a MnO-assisted photosynthetic bacteria (PSB) biohybrid (MnO@PSB) is developed to enhance tumor photothermal immunotherapy by interfering with the Ado-A2AR metabolic pathway. Specifically, manganese dioxide (MnO) nanoflowers are conjugated onto PSB by the carbodiimide reaction to construct the biohybrid MnO@PSB.

Perturbing Organelle-Level K/Ca Homeostasis by Nanotherapeutics for Enhancing Ion-Mediated Cancer Immunotherapy.

Intracellular ions are involved in numerous pivotal immune processes, but the precise regulation of these signaling ions to achieve innovative immune therapeutic strategies is still a huge challenge. Here, an ion-mediated immunotherapy agent (IMIA) is engineered to achieve precise spatiotemporal control of perturbing K/Ca homeostasis at the organelle-level, thereby amplifying antitumor immune responses to achieve high-performance cancer therapy. By taking in intracellular K and supplying exogenous Ca within tumor cells, K/Ca homeostasis is perturbed by IMIA.

Engineered Bdellovibrio bacteriovorus enhances antibiotic penetration and biofilm eradication.

Biofilms increase bacterial resistance to antibiotics, as conventional antibiotic doses are often ineffective at penetrating the biofilm matrix to eliminate bacteria. Recent research has shown that the Gram-negative predator bacterium Bdellovibrio bacteriovorus can penetrate Gram-positive bacterial biofilms during its predation phase and benefit from them without direct predation. Here, based on the penetration ability of B.

Engineered enhances bone regeneration via immunoregulation and anti-Infection.

Chronic osteomyelitis caused by implant infections is a common complication following orthopedic surgery. Preventing bacterial infection and simultaneously improving bone regeneration are the key for osteomyelitis. Current treatments include systemic antibiotics and multiple surgical interventions, but the strategies available for treatment are limited.

A straightforward process manipulates the dramatic morphological changes of DNA rolling circle amplification products.

Rolling circle amplification (RCA) is a widely used method for the synthesis of DNA nanoparticles and macro-hydrogels. Several strategies, including oscillation-promoted entanglement of DNA chains, multi-round chain amplification, hybridization between DNA chains, and hybridization with functional moieties, were applied to synthesize DNA macro-hydrogels; alternatively, flower-like nanoparticles were also produced. Here we report a straightforward yet effective method to manipulate the morphology of RCA products from nanoparticles to 3D hydrogels using an additional cold treatment step of the circular DNA template prior to elongation using phi29 DNA polymerase.

Bimetallic nanoreactor mediates cascade amplification of oxidative stress for complementary chemodynamic-immunotherapy of tumor.

As a promising tumor treatment, chemodynamic therapy (CDT) can specifically catalyze HO into the cytotoxic hydroxyl radical (·OH) via Fenton/Fenton-like reaction. However, the limited HO and weakly acidic pH in tumor microenvironment (TME) would severely restrict the therapeutic efficiency of CDT. Here, a weakly acid activated, HO self-supplied, hyaluronic acid (HA)-functionalized Ce/Cu bimetallic nanoreactor (CBPNs@HA) is elaborately designed for complementary chemodynamic-immunotherapy.