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.

Enhanced nitrogen and phosphorus removal by a novel ecological floating bed integrated with three-dimensional biofilm electrode system.

The ecological floating bed (EFB) has been used extensively for the purification of eutrophication water. However, the traditional EFB (T-EFB) often exhibits a decline in nitrogen and phosphorus removal because of the limited adsorption capacity of fillers and inadequate electron donors. In the present study, a series of electrolysis-ecological floating beds (EC-EFBs) were constructed to investigate the decontamination performance of conventional pollutants.

Leisure sedentary behaviour increases the risk of venous thromboembolism: a Mendelian randomisation study.

Background: Venous thromboembolism (VTE) is a substantial contributor to the global burden of disease. Observational studies have suggested that leisure sedentary behaviours (LSB) are related to the risk of VTE; however, the causal role of LSB in VTE remains unclear.

Methods: Using data obtained from genome-wide association studies in the UK Biobank (N = 422,218), we identified 84, 21, and 4 single nucleotide polymorphisms (SNPs) related to sedentary television (TV) watching, computer use, and driving, respectively.

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.

Syphilis mimetic nanoparticles for cuproptosis-based synergistic cancer therapy via reprogramming copper metabolism.

Small cell lung cancer (SCLC) is one of the most devastating type of human lung cancer and has a high propensity to metastasize into the brain. Cuproptosis recently has been defined as a copper dependent cell death, offers a new lens to develop the novel copper-based nanostructure inducing cuproptosis for suppressing tumor growth and metastasis. Here, we report a syphilis mimetic TP0751-peptide decorated stem cell membrane-coated copper-based metal organic framework (Cu-MOF) nanodelivery system for SCLC brain metastasis.

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).

Metabolic Modulation of Intracellular Ammonia via Intravesical Instillation of Nanoporter-Encased Hydrogel Eradicates Bladder Carcinoma.

Tumor protein 53 (TP53) mutation in bladder carcinoma (BC), upregulates the transcription of carbamoyl phosphate synthetase 1 (CPS1), to reduce intracellular ammonia toxicity. To leverage ammonia combating BC, here, an intravesically perfusable nanoporter-encased hydrogel system is reported. A biomimetic fusogenic liposomalized nanoporter (FLNP) that is decorated with urea transporter-B (UT-B) is first synthesized with protonated chitosan oligosaccharide for bladder tumor-targeted co-delivery of urease and small interfering RNA targeting CPS1 (siCPS1).

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.

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.