Synthetic efferocytic receptor microglia enhances anti-inflammatory clearance of amyloid-β for AD treatment in mice.

Monoclonal antibody immunotherapy targeting the clearance of amyloid-β (Aβ) has shown promise in Alzheimer's disease (AD). However, current antibody treatments trigger Fc receptors and induce proinflammatory responses, in turn exacerbating neuronal damage. Here, we report a synthetic efferocytic receptor (SER) integrating Aβ-targeting scFv, efferocytosis receptor backbone based on TIM4 and downstream signal for microglia (MG) reprogramming, which enabled selective elimination of Aβ without inducing an inflammatory response.

An in situ engineered chimeric IL-2 receptor potentiates the tumoricidal activity of proinflammatory CAR macrophages in renal cell carcinoma.

Chimeric antigen receptor macrophage (CAR-M) therapy has shown great promise in solid malignancies; however, the phenotypic re-domestication of CAR-Ms in the immunosuppressive tumor niche restricts their antitumor immunity. We here report an in situ engineered chimeric interleukin (IL)-2 signaling receptor (CSR) for controllably manipulating the proinflammatory phenotype of CAR-Ms, augmenting their sustained tumoricidal immunity. Specifically, our in-house-customized lipid nanoparticles efficiently introduce dual circular RNAs into macrophages to generate CSR-functionalized CAR-Ms.

Legumain In Situ Engineering Promotes Efferocytosis of CAR Macrophage to Treat Cardiac Fibrosis.

Uncontrolled and excessive cardiac fibrosis after myocardial infarction (MI) is a primary contributor to mortality by heart failure. Chimeric antigen receptor macrophage (CAR-MΦ) therapy shows great promise in cardiac fibrosis, however, the overwhelming apoptotic cells after MI results in an overburdened efferocytosis in CAR-MΦ, which compromises their antifibrotic potency. This work here reports an in situ engineered legumain (Lgmn) to elevate the cargo degradation of phagolysosome for promoting the efferocytosis of CAR-MΦs, restoring their antifibrotic capability.

Rejuvenation Modulation of Nucleus Pulposus Progenitor Cells Reverses Senescence-Associated Intervertebral Disc Degeneration.

The decreased regeneration potential of aging nucleus pulposus resident progenitor cells (NPPCs) fails to resist intervertebral disc degeneration (IVDD), and strategies to remodel the regeneration capacity of senescent NPPC are urgently needed. A decrease in Klotho gene expression in NPPCs of both old mice and humans exacerbates the impaired regenerative functionality of NPPC. Here, an NPPC-targeted lipid thymine nanoparticle (NT-LNP) is reported for the in situ manipulation of the regenerative repair potential of NPPCs, restoration of degenerated nucleus pulposus tissue, and mitigation of IVDD.

Exploration of Optical Fiber and Laser Cutting Head Applications in High-Radiation Environments for Fast Reactor Spent Fuel Reprocessing.

Fast-neutron reactors are an important representative of Generation IV nuclear reactors, and due to the unique structure and material properties of fast reactor fuel, traditional mechanical cutting methods are not applicable. In contrast, laser cutting has emerged as an ideal alternative. However, ensuring the stability of optical fibers and laser cutting heads under high radiation doses, as well as maintaining cutting quality after irradiation, remains a significant technical challenge.

Experimental study on laser cutting process of simulated fast Reactor fuel rods.

The cladding of fast reactor fuel rods, made of stainless steel, presents significant challenges in cutting due to its ductility, which leads to increased tool wear and poor cut quality with traditional mechanical methods. Laser cutting has emerged as a superior alternative, offering non-contact precision, high efficiency, and suitability for radioactive environments. This study systematically investigates the effects of laser cutting parameters-cutting speed, focal position, power, and gas pressure-on the cutting quality of simulated fast reactor fuel rods.

Regulation of the PD-1/PD-L1 Axis and NK Cell Dysfunction by Exosomal miR-552-5p in Gastric Cancer.

Objective: NK cells play a vital role in tumor immune resistance. Various factors affect NK cell activity. While NK cell dysfunction has been observed in numerous malignancies, the underlying mechanisms in gastric cancer remain unclear.

Realveolarization with inhalable mucus-penetrating lipid nanoparticles for the treatment of pulmonary fibrosis in mice.

The stemness loss-associated dysregeneration of impaired alveolar type 2 epithelial (AT2) cells abolishes the reversible therapy of idiopathic pulmonary fibrosis (IPF). We here report an inhalable mucus-penetrating lipid nanoparticle (LNP) for codelivering dual mRNAs, promoting realveolarization via restoring AT2 stemness for IPF treatment. Inhalable LNPs were first formulated with dipalmitoylphosphatidylcholine and our in-house-made ionizable lipids for high-efficiency pulmonary mucus penetration and codelivery of dual messenger RNAs (mRNAs), encoding cytochrome b5 reductase 3 and bone morphogenetic protein 4, respectively.

mRNA-Laden Lipid-Nanoparticle-Enabled CAR-Macrophage Engineering for the Eradication of Multidrug-Resistant Bacteria in a Sepsis Mouse Model.

Sepsis, which is the most severe clinical manifestation of acute infection and has a mortality rate higher than that of cancer, represents a significant global public health burden. Persistent methicillin-resistant (MRSA) infection and further host immune paralysis are the leading causes of sepsis-associated death, but limited clinical interventions that target sepsis have failed to effectively restore immune homeostasis to enable complete eradication of MRSA. To restimulate anti-MRSA innate immunity, we developed CRV peptide-modified lipid nanoparticles (CRV/LNP-RNAs) for transient programming of macrophages (MΦs).

Intracavitary Spraying of Nanoregulator-Encased Hydrogel Modulates Cholesterol Metabolism of Glioma-Supportive Macrophage for Postoperative Glioblastoma Immunotherapy.

Glioblastoma multiforme (GBM) is notoriously resistant to immunotherapy due to its intricate immunosuppressive tumor microenvironment (TME). Dysregulated cholesterol metabolism is implicated in the TME and promotes tumor progression. Here, it is found that cholesterol levels in GBM tissues are abnormally high, and glioma-supportive macrophages (GSMs), an essential "cholesterol factory", demonstrate aberrantly hyperactive cholesterol metabolism and efflux, providing cholesterol to fuel GBM growth and induce CD8 T cells exhaustion.

Dual mRNA co-delivery for in situ generation of phagocytosis-enhanced CAR macrophages augments hepatocellular carcinoma immunotherapy.

Hepatocellular carcinoma (HCC) is a prevalent and lethal disease, and tumor regression rarely occurs in advanced HCC patients due to limited effective therapies. Given the enrichment of macrophages in HCC and their role in tumor immunity, transforming them into chimeric antigen receptor macrophages (CAR-Ms) is thought to increase HCC cell-directed phagocytosis and tumoricidal immunity. To test this hypothesis, mRNA encoding CAR is encapsulated in a lipid nanoparticle (LNP) that targets liver macrophages.

Surficial nano-deposition locoregionally yielding bactericidal super CAR-macrophages expedites periprosthetic osseointegration.

Tracking and eradicating in the periprosthetic microenvironment are critical for preventing periprosthetic joint infection (PJI), yet effective strategies remain elusive. Here, we report an implant nanoparticle coating that locoregionally yields bactericidal super chimeric antigen receptor macrophages (CAR-MΦs) to prevent PJI. We demonstrate that the plasmid-laden nanoparticle from the coating can introduce -targeted CAR genes and caspase-11 short hairpin RNA (CASP11 shRNA) into macrophage nuclei to generate super CAR-MΦs in mouse models.

Reversing immune evasion using a DNA nano-orchestrator for pancreatic cancer immunotherapy.

Immune evasion caused by the paucity of MHCI is a prominent characteristic of pancreatic adenocarcinoma (PAAD), which is thought to underlie dysfunctional even absent adaptive T cell immunity and is responsible for ineffective immunotherapy. Here, we report a ROS-responsive DNA nano-orchestrator to cascade reverse MHC I-associated immune evasion and boost anti-tumor T cell stimulation, stimulating the activation of tumoricidal immunity against PAAD. Chloroquine phosphate (CQP) as an autophagy inhibitor was first encapsulated with ferritin, and via DNA modular self-assembly technology, the generated ferritin nanocores (FNC) were then caged into ROS-responsive CpG-DNA nanoframe.

Cell membrane derived liposomes loaded with DNase I target neutrophil extracellular traps which inhibits colorectal cancer liver metastases.

Neutrophil extracellular traps (NETs) are web-like chromatin structures that are coated with granule proteins and trap microorganisms. However, NETs can damage the host tissue, contribute to the development of autoimmunity and lead to other dysfunctional outcomes in noninfectious diseases, including systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), diabetes, atherosclerosis, vasculitis, thrombosis, and cancer. As a potential therapeutic approach, targeted ablation of neutrophil extracellular traps is of utmost importance for the treatment of NET-associated diseases.

Convection-enhanced delivery of nanoencapsulated gene locoregionally yielding ErbB2/Her2-specific CAR-macrophages for brainstem glioma immunotherapy.

Locoregional delivery of chimeric antigen receptor (CAR)-modified T (CAR-T) cells has emerged as a promising strategy for brain tumors. However, the complicated ex vivo cell manufacturing procedures and the rapid progression of the disease have limited its broader applications. Macrophages (MΦs) exhibit unique effector functions and a high degree of infiltration within the solid tumor microenvironment (TME), especially in the brain, where MΦs function as structural support, and the main immune effector cells of the CNS represent 5-12% of brain cells.

Remodeling articular immune homeostasis with an efferocytosis-informed nanoimitator mitigates rheumatoid arthritis in mice.

Massive intra-articular infiltration of proinflammatory macrophages is a prominent feature of rheumatoid arthritis (RA) lesions, which are thought to underlie articular immune dysfunction, severe synovitis and ultimately joint erosion. Here we report an efferocytosis-informed nanoimitator (EINI) for in situ targeted reprogramming of synovial inflammatory macrophages (SIMs) that thwarts their autoimmune attack and reestablishes articular immune homeostasis, which mitigates RA. The EINI consists of a drug-based core with an oxidative stress-responsive phosphatidylserine (PtdSer) corona and a shell composed of a P-selectin-blocking motif, low molecular weight heparin (LMWH).

Trojan Horse Nanocapsule Enabled In Situ Modulation of the Phenotypic Conversion of Th17 Cells to Treg Cells for the Treatment of Multiple Sclerosis in Mice.

Th17/Treg imbalance is closely related to the occurrence and development of multiple sclerosis (MS), and the transdifferentiation of Th17 cells into Treg cells may contribute to the resolution of inflammation, presenting a therapeutic strategy for MS. To modulate this phenotypic shift in situ, a "Trojan horse"-like hybrid system, nanocapsule-coupled Th17 cells, is reported for MS treatment. Following intravenous injection into MS mice, the hybrid system efficiently transmigrates across the blood-brain barrier and homes to the inflamed MS niche.

Intracavity generation of glioma stem cell-specific CAR macrophages primes locoregional immunity for postoperative glioblastoma therapy.

Glioblastoma multiforme (GBM) remains incurable despite aggressive implementation of multimodal treatments after surgical debulking. Almost all patients with GBM relapse within a narrow margin around the initial resected lesion due to postsurgery residual glioma stem cells (GSCs). Tracking and eradicating postsurgery residual GSCs is critical for preventing postoperative relapse of this devastating disease, yet effective strategies remain elusive.

Inhaled mRNA Nanoformulation with Biogenic Ribosomal Protein Reverses Established Pulmonary Fibrosis in a Bleomycin-Induced Murine Model.

Idiopathic pulmonary fibrosis (IPF), a lethal respiratory disease with few treatment options, occurs due to repetitive microinjuries to alveolar epithelial cells (AECs) and progresses with an overwhelming deposition of extracellular matrix (ECM), ultimately resulting in fibrotic scars and destroyed the alveolar architecture. Here, an inhaled ribosomal protein-based mRNA nanoformulation is reported for clearing the intrapulmonary ECM and re-epithelializing the disrupted alveolar epithelium, thereby reversing established fibrotic foci in IPF. The nanoformulation is sequentially assembled by a ribosomal protein-condensed mRNA core, a bifunctional peptide-modified corona and keratinocyte growth factor (KGF) with a PEGylated shielding shell.

tuning proangiogenic factor-mediated immunotolerance synergizes the tumoricidal immunity via a hypoxia-triggerable liposomal bio-nanoreactor.

Vascular abnormality stemming from the hypoxia-driven elevation of proangiogenic factors is a hallmark for many solid malignant tumors, including colorectal cancer (CRC) and its liver metastasis. We report a hypoxia-triggered liposome-supported metal-polyphenol-gene bio-nanoreactor to tune the proangiogenic factor-mediated immunotolerance and synergize the elicited tumoricidal immunity for CRC treatment. With the aid of polyphenol gallic acid, Cu ion-based intracellular bio-nanoreactor was synthesized for the delivery of small interfering RNA targeting vascular endothelial growth factor and then cloaked with a hybrid liposomal membrane that harbored a hypoxia-responsive azobenzene derivative.

Morphological and hemodynamic changes of sciatic nerves and their vasa nervorum during circular compression and relaxation.

The main aim of this study was to evaluate the biomechanical and hemodynamic responses of vasa nervorum under transverse circular compression. In situ compress-and-hold experiments were performed on the sciatic nerves of healthy and diabetic rats, and the blood flow within the vasa nervorum was observed using Doppler-optical coherence tomography. A new technique was developed to obtain the time-course of the cross sectional area and the morphology of the vasa nervorum from the tomographic images.

Efficiently restoring the tumoricidal immunity against resistant malignancies via an immune nanomodulator.

Bioinformatically triple negative breast cancer (TNBC) and colon adenocarcinoma (COAD), two typical "cold" cancers, were found overexpressed PD-L1 and CD47 respectively but neither of them showed satisfied response on its corresponding immune checkpoint blockade (ICB) in clinic. The initial immunotherapeutic resistance to ICB was essentially attributed to the so-called "cold" tumor immune milieu (TIM). To overcome tumor immunological tolerance against ICBs, here we report a versatile nano-modulator for point-to-point counteracting the immune-suppressors meanwhile boosting tumor T cell infiltration.