Ag
ions are a well-known antibacterial agent, and Ag nanoparticles act as a reservoir of these Ag
ions for targeted therapy of bacterial infections. However, there are no tools to effectively trigger ...and monitor the release of Ag
ions from Ag nanoparticles. Photoacoustic (PA) imaging is an emerging noninvasive imaging tool, and gold nanorods (AuNRs) are an excellent contrast agent for PA imaging. In this work, we developed Au/Ag hybrid nanoparticles by coating AuNRs with silver (Ag), which decreased their photoacoustic signal. The as-prepared, Ag-coated Au nanorods (Au/AgNRs) are stable under ambient conditions, but the addition of ferricyanide solution (1 mM) results in oxidative etching of the silver shell. The PA contrast is simultaneously recovered as the silver is released, and this PA signal offers noninvasive monitoring of localized release of Ag
ions. The released Ag
ions exhibit a strong bactericidal efficacy similar to equivalent free Ag
ions (AgNO
), and the nanoparticles killed >99.99% of both (Gram-positive) methicillin-resistant Staphylococcus aureus (MRSA, 32 μM Ag
equivalent) and (Gram-negative) Escherichia coli (8 μM Ag
equivalent). The theranostic potential of these nanoparticles was demonstrated in a pilot in vivo study. Mice were inoculated with MRSA and Au/AgNRs were subcutaneously implanted followed by silver etching. There was a 730% increase in the PA signal ( p < 0.01) pre- and post-etching, and the bacterial counts in infected tissues of the treated group were reduced by 1000-fold (log CFU/g = 4.15 vs 7.75) versus the untreated control; this treatment efficacy was confirmed with histology. We further showed that these hybrid nanoparticles could release Ag
after stimulation by reactive oxygen species including hydrogen peroxide and peroxynitrite. These hybrid Au/Ag nanoparticles are a useful theranostic agent for the photoacoustic imaging and treatment of bacterial infections.
Abstract
Acute pancreatitis is a disease associated with suffering and high lethality. Although the disease mechanism is unclear, phospholipase A2 (PLA2) produced by pancreatic acinar cells is a ...known pathogenic trigger. Here, we show macrophage membrane-coated nanoparticles with a built-in ‘lure and kill’ mechanism (denoted ‘MΦ-NP(L&K)’) for the treatment of acute pancreatitis. MΦ-NP(L&K) are made with polymeric cores wrapped with natural macrophage membrane doped with melittin and MJ-33. The membrane incorporated melittin and MJ-33 function as a PLA2 attractant and a PLA2 inhibitor, respectively. These molecules, together with membrane lipids, work synergistically to lure and kill PLA2 enzymes. These nanoparticles can neutralize PLA2 activity in the sera of mice and human patients with acute pancreatitis in a dose-dependent manner and suppress PLA2-induced inflammatory response accordingly. In mouse models of both mild and severe acute pancreatitis, MΦ-NP(L&K) confer effective protection against disease-associated inflammation, tissue damage and lethality. Overall, this biomimetic nanotherapeutic strategy offers an anti-PLA2 treatment option that might be applicable to a wide range of PLA2-mediated inflammatory disorders.
Sepsis, resulting from uncontrolled inflammatory responses to bacterial infections, continues to cause high morbidity and mortality worldwide. Currently, effective sepsis treatments are lacking in ...the clinic, and care remains primarily supportive. Here we report the development of macrophage biomimetic nanoparticles for the management of sepsis. The nanoparticles, made by wrapping polymeric cores with cell membrane derived from macrophages, possess an antigenic exterior the same as the source cells. By acting as macrophage decoys, these nanoparticles bind and neutralize endotoxins that would otherwise trigger immune activation. In addition, these macrophage-like nanoparticles sequester proinflammatory cytokines and inhibit their ability to potentiate the sepsis cascade. In a mouse Escherichia coli bacteremia model, treatment with macrophage mimicking nanoparticles, termed MΦ-NPs, reduced proinflammatory cytokine levels, inhibited bacterial dissemination, and ultimately conferred a significant survival advantage to infected mice. Employing MΦ-NPs as a biomimetic detoxification strategy shows promise for improving patient outcomes, potentially shifting the current paradigm of sepsis management.
Synthetic nanoparticles coated with cellular membranes have been increasingly explored to harness natural cell functions toward the development of novel therapeutic strategies. Herein, we report on a ...unique bacterial membrane-coated nanoparticle system as a new and exciting antibacterial vaccine. Using Escherichia coli as a model pathogen, we collect bacterial outer membrane vesicles (OMVs) and successfully coat them onto small gold nanoparticles (AuNPs) with a diameter of 30 nm. The resulting bacterial membrane-coated AuNPs (BM-AuNPs) show markedly enhanced stability in biological buffer solutions. When injected subcutaneously, the BM-AuNPs induce rapid activation and maturation of dendritic cells in the lymph nodes of the vaccinated mice. In addition, vaccination with BM-AuNPs generates antibody responses that are durable and of higher avidity than those elicited by OMVs only. The BM-AuNPs also induce an elevated production of interferon gamma (INFγ) and interleukin-17 (IL-17), but not interleukin-4 (IL-4), indicating its capability of generating strong Th1 and Th17 biased cell responses against the source bacteria. These observed results demonstrate that using natural bacterial membranes to coat synthetic nanoparticles holds great promise for designing effective antibacterial vaccines.
Small interfering RNA (siRNA) is a powerful tool for gene silencing that has been used for a wide range of biomedical applications, but there are many challenges facing its therapeutic use in vivo. ...Here, we report on a platelet cell membrane-coated metal-organic framework (MOF) nanodelivery platform for the targeted delivery of siRNA in vivo. The MOF core is capable of high loading yields, and its pH sensitivity enables endosomal disruption upon cellular uptake. The cell membrane coating provides a natural means of biointerfacing with disease substrates. It is shown that high silencing efficiency can be achieved in vitro against multiple target genes. Using a murine xenograft model, significant antitumor targeting and therapeutic efficacy are observed. Overall, the biomimetic nanodelivery system presented here provides an effective means of achieving gene silencing in vivo and could be used to expand the applicability of siRNA across a range of disease-relevant applications.
Platelets exhibit distinct surface moieties responsible for modulating their adhesion to various disease‐relevant substrates involving vascular damage, immune evasion, and pathogen interactions. Such ...broad biointerfacing capabilities of platelets have inspired the development of platelet‐mimicking drug carriers that preferentially target drug payloads to disease sites for enhanced therapeutic efficacy. Among these carriers, platelet membrane–coated nanoparticles (denoted “PNPs”) made by cloaking synthetic substrates with the plasma membrane of platelets have emerged recently. Their “top‐down” design combines the functionalities of natural platelet membrane and the engineering flexibility of synthetic nanomaterials, which together create synergy for effective drug delivery and novel therapeutics. Herein, the recent progress of engineering PNPs with different structures for targeted drug delivery is reviewed, focusing on three areas, including targeting injured blood vessels to treat vascular diseases, targeting cancer cells for cancer treatment and detection, and targeting drug‐resistant bacteria to treat infectious diseases. Overall, current studies establish PNPs as versatile nanotherapeutics for drug targeting with strong potentials to improve the treatment of various diseases.
Platelet membrane–coated nanoparticles inherit biofunctions of natural platelets and are capable of adhering to various disease‐relevant substrates. They have become drug carriers exceptionally suitable for targeted drug delivery. Herein, the recent development of platelet‐mimicking nanoparticles with different structures for drug targeting to injured blood vessels, cancer cells, and drug‐resistant bacteria is reviewed.
Inhibition of phospholipase A2 (PLA2) has long been considered for treating various diseases associated with an elevated PLA2 activity. However, safe and effective PLA2 inhibitors remain unavailable. ...Herein, we report a biomimetic nanoparticle design that enables a “lure and kill” mechanism designed for PLA2 inhibition (denoted “L&K‐NP”). The L&K‐NPs are made of polymeric cores wrapped with modified red blood cell membrane with two inserted key components: melittin and oleyloxyethyl phosphorylcholine (OOPC). Melittin acts as a PLA2 attractant that works together with the membrane lipids to “lure” in‐coming PLA2 for attack. Meanwhile, OOPC acts as inhibitor that “kills” PLA2 upon enzymatic attack. Both compounds are integrated into the L&K‐NP structure, which voids toxicity associated with free molecules. In the study, L&K‐NPs effectively inhibit PLA2‐induced hemolysis. In mice administered with a lethal dose of venomous PLA2, L&K‐NPs also inhibit hemolysis and confer a significant survival benefit. Furthermore, L&K‐NPs show no obvious toxicity in mice. and the design provides a platform technology for a safe and effective anti‐PLA2 approach.
Modified red blood cell membrane is used to fabricate a cell‐like nanoparticle for safe and effective inhibition of phospholipase A2 (PLA2) based on a “lure and kill” working mechanism. The resulting nanoparticle can attract the PLA2 enzyme and subsequently inhibit its bioactivity. As a result, the nanoparticle can effectively inhibit PLA2‐induced hemolysis and protect animals from PLA2‐induced lethality.
Although myocyte cell transplantation studies have suggested a promising therapeutic potential for myocardial infarction, a major obstacle to the development of clinical therapies for myocardial ...repair is the difficulties associated with obtaining relatively homogeneous ventricular myocytes for transplantation. Human embryonic stem cells （hESCs） are a promising source of cardiomyocytes. Here we report that retinoid signaling regulates the fate specification of atrial versus ventricular myocytes during cardiac differentiation of hESCs. We found that both Noggin and the panretinoic acid receptor antagonist BMS-189453 （RAi） significantly increased the cardiac differentiation efficiency of hESCs. To investigate retinoid functions, we compared Noggin＋RAi-treated cultures with Noggin＋RA-treated cul- tures. Our results showed that the expression levels of the ventricular-specific gene IRX-4 were radically elevated in Noggin＋RAi-treated cultures. MLC-2V, another ventricular-specific marker, was expressed in the majority of the cardiomyocytes in Noggin＋RAi-treated cultures, but not in the cardiomyocytes of Noggin＋RA-treated cultures. Flow cytometry analysis and electrophysiological studies indicated that with 64.7 ±0.88% （mean ± s.e.m） cardiac differen- tiation efficiency, 83% of the cardiomyocytes in Noggin＋RAi-treated cultures had embryonic ventricular-llke action potentials （APs）. With 50.7 ± 1.76% cardiac differentiation efficiency, 94% of the cardiomyocytes in Noggin＋RA- treated cultures had embryonic atrial-like APs. These results were further confirmed by imaging studies that assessed the patterns and properties of the Ca^2＋ sparks of the cardiomyocytes from the two cultures. These findings demonstrate that retinoid signaling specifies the atrial versus ventricular differentiation of hESCs. This study also shows that relatively homogeneous embryonic atrial- and ventricular-like myocyte populations can be efficiently derived from hESCs by specifically regulating Noggin and retinoid signals.
Background:
Non–small cell lung cancer (NSCLC) is highly malignant with driver somatic mutations and genomic instability. Long non-coding RNAs (lncRNAs) play a vital role in regulating these two ...aspects. However, the identification of somatic mutation-derived, genomic instability-related lncRNAs (GIRlncRNAs) and their clinical significance in NSCLC remains largely unexplored.
Methods:
Clinical information, gene mutation, and lncRNA expression data were extracted from TCGA database. GIRlncRNAs were screened by a mutator hypothesis-derived computational frame. Co-expression, GO, and KEGG enrichment analyses were performed to investigate the biological functions. Cox and LASSO regression analyses were performed to create a prognostic risk model based on the GIRlncRNA signature (GIRlncSig). The prediction efficiency of the model was evaluated by using correlation analyses with mutation, driver gene, immune microenvironment contexture, and therapeutic response. The prognostic performance of the model was evaluated by external datasets. A nomogram was established and validated in the testing set and TCGA dataset.
Results:
A total of 1446 GIRlncRNAs were selected from the screen, and the established GIRlncSig was used to classify patients into high- and low-risk groups. Enrichment analyses showed that GIRlncRNAs were mainly associated with nucleic acid metabolism and DNA damage repair pathways. Cox analyses further identified 19 GIRlncRNAs to construct a GIRlncSig-based risk score model. According to Cox regression and stratification analyses, 14 risk lncRNAs (AC023824.3, AC013287.1, AP000829.1, LINC01611, AC097451.1, AC025419.1, AC079949.2, LINC01600, AC004862.1, AC021594.1, MYRF-AS1, LINC02434, LINC02412, and LINC00337) and five protective lncRNAs (LINC01067, AC012645.1, AL512604.3, AC008278.2, and AC089998.1) were considered powerful predictors. Analyses of the model showed that these GIRlncRNAs were correlated with somatic mutation pattern, immune microenvironment infiltration, immunotherapeutic response, drug sensitivity, and survival of NSCLC patients. The GIRlncSig risk score model demonstrated good predictive performance (AUCs of ROC for 10-year survival was 0.69) and prognostic value in different NSCLC datasets. The nomogram comprising GIRlncSig and tumor stage exhibited improved robustness and feasibility for predicting NSCLC prognosis.
Conclusion:
The newly identified GIRlncRNAs are powerful biomarkers for clinical outcome and prognosis of NSCLC. Our study highlights that the GIRlncSig-based score model may be a useful tool for risk stratification and management of NSCLC patients, which deserves further evaluation in future prospective studies.
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