Application of a derivative of human defensin 5 to treat ionizing radiation-induced enterogenic infection.

Enterogenic infection is a common complication for patients with radiation injury and requires efficient therapeutics in the clinic. Herein, we evaluated the promising drug candidate T7E21RHD5, which is a peptide derived from intestinal Paneth cell-secreted human defensin 5. Oral administration of this peptide alleviated the diarrhea symptoms of mice that received total abdominal irradiation (TAI, γ-ray, 12 Gy) and improved survival. Pathologic analysis revealed that T7E21RHD5 elicited an obvious mitigation of ionizing radiation (IR)-induced epithelial damage and ameliorated the reduction in the levels of claudin, zonula occluden 1 and occludin, three tight junction proteins in the ileum. Additionally, T7E21RHD5 regulated the gut microbiota in TAI mice by remodeling ß diversity, manifested as a reversal of the inverted proportion of Bacteroidota to Firmicutes caused by IR. T7E21RHD5 treatment also decreased the abundance of pathogenic Escherichia-Shigella but significantly increased the levels of Alloprevotella and Prevotellaceae_NK3B31, two short-chain fatty acid-producing bacterial genera in the gut. Accordingly, the translocation of enterobacteria and lipopolysaccharide to the blood, as well as the infectious inflammatory responses in the intestine after TAI, was all suppressed by T7E21RHD5 administration. Hence, this versatile antimicrobial peptide possesses promising application prospects in the treatment of IR-induced enterogenic infection.

Intrinsically bioactive and biomimetic nanoparticle-derived therapies alleviate asthma by regulating multiple pathological cells.

Asthma is a serious global public health concern. Airway neutrophilic inflammation is closely related to severe asthma, for which effective and safe therapies remain to be developed. Here we report nanotherapies capable of simultaneously regulating multiple target cells relevant to the pathogenesis of neutrophilic asthma. A nanotherapy LaCD NP based on a cyclic oligosaccharide-derived bioactive material was engineered. LaCD NP effectively accumulated in the injured lungs of asthmatic mice and mainly distributed in neutrophils, macrophages, and airway epithelial cells after intravenous or inhalation delivery, thereby ameliorating asthmatic symptoms and attenuating pulmonary neutrophilic inflammation as well as reducing airway hyperresponsiveness, remodeling, and mucus production. Surface engineering via neutrophil cell membrane further enhanced targeting and therapeutic effects of LaCD NP. Mechanistically, LaCD NP can inhibit the recruitment and activation of neutrophils, especially reducing the neutrophil extracellular traps formation and NLRP3 inflammasome activation in neutrophils. Also, LaCD NP can suppress macrophage-mediated pro-inflammatory responses and prevent airway epithelial cell death and smooth muscle cell proliferation, by mitigating neutrophilic inflammation and its direct effects on relevant cells. Importantly, LaCD NP showed good safety performance. Consequently, LaCD-derived multi-bioactive nanotherapies are promising for effective treatment of neutrophilic asthma and other neutrophil-associated diseases.

Clustered Cobalt Nanodots Initiate Ferroptosis by Upregulating Heme Oxygenase 1 for Radiotherapy Sensitization.

High cobalt (Co) levels in tumors are associated with good clinical prognosis. An anticancer regimen that increases intratumoral Co through targeted nanomaterial delivery is proposed in this study. Bovine serum albumin and cobalt dichloride are applied to prepare cobaltous oxide nanodots using a facile biomineralization strategy. After iRGD peptide conjugation, the nanodots are loaded into dendritic mesoporous silica nanoparticles, generating a biocompatible product iCoDMSN. This nanocomposite accumulates in tumors after intravenous injection by deep tissue penetration and can be used for photoacoustic imaging. Proteomics research and molecular biology experiments reveal that iCoDMSN is a potent ferroptosis inducer in cancer cells. Mechanistically, iCoDMSNs upregulate heme oxygenase 1 (HMOX1), which increases transferrin receptors and reduces solute carrier family 40 member 1 (SLC40A1), resulting in Fe2+ accumulation and ferroptosis initiation. Furthermore, upregulated nuclear factor erythroid 2-related factor 2 (NRF2), arising from the reduction in Kelch-like ECH-associated protein 1 (KEAP1) expression, is responsible for HMOX1 enhancement after iCoDMSN treatment. Owing to intensified ferroptosis, iCoDMSN acts as an efficient radiotherapy enhancer to eliminate cancer cells in vitro and in vivo. This study demonstrates a versatile Co-based nanomaterial that primes ferroptosis by expanding the labile iron pool in cancer cells, providing a promising tumor radiotherapy sensitizer.

Irradiation accelerates SARS-CoV-2 infection by enhancing sphingolipid metabolism.

Cancer patients who receive radiotherapy have a high risk of severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) infection, but the concrete reason remains unclear. Herein, we investigated the influence of irradiation on the vulnerability of cancer cells to SARS-CoV-2 using S pseudovirions and probed the underlying mechanism via RNA-seq and other molecular biology techniques. Owing to the enhancement of sphingolipid metabolism, irradiation accelerated pseudovirion infection. Mechanistically, irradiation induced the expression of acid sphingomyelinase (ASM), which catalyses the hydrolysis of sphingomyelin to ceramide, contributing to lipid raft formation and promoting SARS-CoV-2 invasion. Inhibition of lipid raft formation with methyl-ß-cyclodextrin (MßCD) or the tyrosine kinase inhibitor genistein and ASM suppression through small interfering RNA or amitriptyline (AMT) treatment abolished the enhancing effect of irradiation on viral infection. Animal experiments supported the finding that irradiation promoted SARS-CoV-2 S pseudovirion infection in A549 cell tumour-bearing BALB/c nude mice, whereas AMT treatment dramatically decreased viral infection. This study discloses the role of sphingolipid metabolism in irradiation-induced SARS-CoV-2 infection, thus providing a potential target for clinical intervention to protect patients receiving radiotherapy from COVID-19.

Selenium nanoparticles alleviate ischemia reperfusion injury-induced acute kidney injury by modulating GPx-1/NLRP3/Caspase-1 pathway.

Rationale: Acute kidney injury (AKI) is a common critical illness in the clinic and currently lacks effective treatment options. Ischemia reperfusion injury (IRI) is a major pathogenic factor for AKI. Due to the deficiency of selenium (Se) in AKI patients, we intended to treat IRI-induced AKI using a Se rebalancing strategy in the present study. Methods: Sodium selenate, ascorbic acid, and bovine serum albumin (BSA) were employed to prepare nanomaterials termed Se@BSA nanoparticles (NPs) using a simple method. Experiments with human renal tubular epithelial HK-2 cells exposed to hypoxia/reoxygenation (H/R) and IRI-AKI mice were used to evaluate the therapeutic efficiency of Se@BSA NPs. Transcriptome sequencing, further molecular biology experiments, and pathologic analysis were performed to investigate the underlying mechanisms. Results: Se@BSA NPs accumulated in mouse kidneys and could be endocytosed by renal tubular epithelial cells after intravenous administration. In vitro studies showed that Se@BSA NP treatment markedly increased the levels of glutathione peroxidase (GPx)-1 and suppressed NLRP3 inflammasome activation in H/R cells, which resulted in reductions in the proteolytic cleavage of pro-Caspase-1 into active Caspase-1 and the maturation of inflammatory factors. Mouse experiments confirmed these findings and demonstrated an inspiring mitigative effect of Se@BSA NPs on IRI-induced AKI. Owing to modulation of the GPx-1/NLRP3/Caspase-1 pathway, Se@BSA NPs dramatically inhibited fibrosis formation after AKI. Conclusion: This study provides an effective therapeutic option by applying easy-to-produce Se-containing nanomaterials to remedy Se imbalance and impede inflammatory responses in the kidney, which is a promising candidate for AKI treatment.

Renal Klotho and inorganic phosphate are extrinsic factors that antagonistically regulate hematopoietic stem cell maintenance.

The composition and origin of extrinsic cues required for hematopoietic stem cell (HSC) maintenance are incompletely understood. Here we identify renal Klotho and inorganic phosphate (Pi) as extrinsic factors that antagonistically regulate HSC maintenance in the bone marrow (BM). Disruption of the Klotho-Pi axis by renal Klotho deficiency or Pi excess causes Pi overload in the BM niche and Pi retention in HSCs, leading to alteration of HSC maintenance. Mechanistically, Pi retention is mediated by soluble carrier family 20 member 1 (SLC20A1) and sensed by diphosphoinositol pentakisphosphate kinase 2 (PPIP5K2) to enhance Akt activation, which then upregulates SLC20A1 to aggravate Pi retention and augments GATA2 activity to drive the expansion and megakaryocyte/myeloid-biased differentiation of HSCs. However, kidney-secreted soluble Klotho directly maintains HSC pool size and differentiation by restraining SLC20A1-mediated Pi absorption of HSCs. These findings uncover a regulatory role of the Klotho-Pi axis orchestrated by the kidneys in BM HSC maintenance.

Hydrogel Transformed from Nanoparticles for Prevention of Tissue Injury and Treatment of Inflammatory Diseases.

Functional hydrogels responsive to physiological and pathological signals have extensive biomedical applications owing to their multiple advanced attributes. Herein, engineering of functional hydrogels is reported via transformable nanoparticles in response to the physiologically and pathologically acidic microenvironment. These nanoparticles are assembled by a multivalent hydrophobic, pH-responsive cyclodextrin host material and a multivalent hydrophilic guest macromolecule. Driven by protons, the pH-responsive host-guest nanoparticles can be transformed into hydrogel, resulting from proton-triggered hydrolysis of the host material, generation of a hydrophilic multivalent host compound, and simultaneously enhanced inclusion interactions between host and guest molecules. By in situ forming a hydrogel barrier, the orally delivered transformable nanoparticles protect mice from ethanol- or drug-induced gastric injury. In addition, this type of nanoparticles can serve as responsive and transformable nanovehicles for therapeutic agents to achieve triggerable and sustained drug delivery, thereby effectively treating typical inflammatory diseases, including periodontitis and arthritis in rats. With combined advantages of nanoparticles and hydrogels, together with their good in vivo safety, the engineered transformable nanoparticles hold great promise in tissue injury protection and site-specific/local delivery of molecular and cellular therapeutic agents.

γ-Core Guided Antibiotic Design Based on Human Enteric Defensin 5.

An increase in the number of infections caused by resistant bacteria worldwide necessitates the development of alternatives to antibiotics. Human defensin (HD) 5 is an innate immune peptide with broad-spectrum antibacterial activity, but its complicated structure makes its preparation difficult. Herein, we truncated the HD5 structure by extracting the highly conserved γ-core motif. A structure-activity study showed that this motif was ineffective in killing bacteria in the absence of specific spatial conformation. Notably, after the introduction of two intramolecular disulfide bonds, its antibacterial activity was markedly improved. Glu and Ser residues were then replaced with Arg to create the derivative RC18, which exhibited stronger potency than HD5, particularly against methicillin-resistant S. aureus (MRSA). Mechanistically, RC18 bound to lipid A and lipoteichoic acid at higher affinities than HD5. Furthermore, RC18 was more efficient than HD5 in penetrating the bacterial membranes. Molecular dynamics simulation revealed that five Arg residues, Arg1, Arg7, Arg9, Arg15, and Arg18, mediated most of the polar interactions of RC18 with the phospholipid head groups during membrane penetration. In vivo experiments indicated that RC18 decreased MRSA colonization and dramatically improved the survival of infected mice, thus demonstrating that RC18 is a promising drug candidate to treat MRSA infections.

A Prognostic Signature Constructed by CTHRC1 and LRFN4 in Stomach Adenocarcinoma.

BACKGROUND: Stomach adenocarcinoma (STAD) is the most common histological type of stomach cancer, which causes a considerable number of deaths worldwide. This study aimed to identify its potential biomarkers with the notion of revealing the underlying molecular mechanisms. METHODS: Gene expression profile microarray data were downloaded from the Gene Expression Omnibus (GEO) database. The "limma" R package was used to screen the differentially expressed genes (DEGs) between STAD and matched normal tissues. The Database for Annotation, Visualization, and Integrated Discovery (DAVID) was used for function enrichment analyses of DEGs. The STAD dataset from The Cancer Genome Atlas (TCGA) database was used to identify a prognostic gene signature, which was verified in another STAD dataset from the GEO database. CIBERSORT algorithm was used to characterize the 22 human immune cell compositions. The expression of LRFN4 and CTHRC1 in tissues was determined by quantitative real-time PCR from the patients recruited to the present study. RESULTS: Three public datasets including 90 STAD patients and 43 healthy controls were analyzed, from which 44 genes were differentially expressed in all three datasets. These genes were implicated in biological processes including cell adhesion, wound healing, and extracellular matrix organization. Five out of 44 genes showed significant survival differences. Among them, CTHRC1 and LRFN4 were selected for construction of prognostic signature by univariate Cox regression and stepwise multivariate Cox regression in the TCGA-STAD dataset. The fidelity of the signature was evaluated in another independent dataset and showed a good classification effect. The infiltration levels of multiple immune cells between high-risk and low-risk groups had significant differences, as well as two immune checkpoints. TIM-3 and PD-L2 were highly correlated with the risk score. Multiple signaling pathways differed between the two groups of patients. At the same time, the expression level of LRFN4 and CTHRC1 in tissues analyzed by quantitative real-time PCR were consistent with the in silico findings. CONCLUSION: The present study constructed the prognostic signature by expression of CTHRC1 and LRFN4 for the first time via comprehensive bioinformatics analysis, which provided the potential therapeutic targets of STAD for clinical treatment.

An angiotensin-converting enzyme-2-derived heptapeptide GK-7 for SARS-CoV-2 spike blockade.

The ongoing coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is a global concern and necessitates efficient drug antagonists. Angiotensin-converting enzyme-2 (ACE2) is the main receptor of SARS-CoV-2 spike 1 (S1), which mediates viral invasion into host cells. Herein, we designed and prepared short peptide inhibitors containing 4-6 critical residues of ACE2 that contribute to the interaction with SARS-CoV-2 S1. Among the candidates, a peptide termed GK-7 (GKGDFRI), which was designed by extracting residues ranging from Gly353 to Ile359 in the ligand-binding domain of ACE2, exhibited the highest binding affinity (25.1 nM) with the SARS-CoV-2 spike receptor-binding domain (RBD). GK-7 bound to the RBD and decreased SARS-CoV-2 S1 attachment to A549 human alveolar epithelial cells. Owing to spike blockade, GK-7 inhibited SARS-CoV-2 spike pseudovirion infection in a dose-dependent manner, with a half-maximal inhibitory concentration of 2.96 µg/mL. Inspiringly, pulmonary delivery of GK-7 by intranasal administration did not result in toxicity in mice. This study revealed an easy-to-produce peptide inhibitor for SARS-CoV-2 spike blockade, thus providing a promising candidate for COVID-19 treatment.

Polyphenol-assisted facile assembly of bioactive nanoparticles for targeted therapy of heart diseases.

It remains a great challenge for targeted therapy of heart diseases. To achieve desirable heart targeting, we developed a polyphenol-assisted nanoprecipitation/self-assembly approach for facile engineering of functional nanoparticles. Three different materials were employed as representative carriers, while gallic acid, catechin, epigallocatechin gallate, and tannic acid (TA) served as typical polyphenols with varied numbers of phenolic hydroxyl groups. By optimizing different parameters, such as polyphenol types and the weight ratio of carrier materials and polyphenols, well-defined nanoparticles with excellent physicochemical properties can be easily prepared. Regardless of various carrier materials, TA-derived nanoparticles showed potent reactive oxygen species-scavenging activity, especially nanoparticles produced from a cyclodextrin-derived bioactive material (TPCD). By internalization into cardiomyocytes, TPCD/TA nanoparticles (defined as TPTN) effectively protected cells from hypoxic-ischemic injury. After intravenous injection, TPTN considerably accumulated in the injured heart in two murine models of ventricular fibrillation cardiac arrest in rats and myocardial hypertrophy in mice. Correspondingly, intravenously delivered TPTN afforded excellent therapeutic effects in both heart diseases. Preliminary experiments also revealed good safety of TPTN. These results substantiated that TPTN is a promising nanotherapy for targeted treatment of heart diseases, while polyphenol-assisted self-assembly is a facile but robust strategy to develop heart-targeting delivery systems.

Human Cathelicidin Inhibits SARS-CoV-2 Infection: Killing Two Birds with One Stone.

SARS-CoV-2 infection begins with the association of its spike 1 (S1) protein with host angiotensin-converting enzyme-2 (ACE2). Targeting the interaction between S1 and ACE2 is a practical strategy against SARS-CoV-2 infection. Herein, we show encouraging results indicating that human cathelicidin LL37 can simultaneously block viral S1 and cloak ACE2. LL37 binds to the receptor-binding domain (RBD) of S1 with high affinity (11.2 nM) and decreases subsequent recruitment of ACE2. Owing to the RBD blockade, LL37 inhibits SARS-CoV-2 S pseudovirion infection, with a half-maximal inhibitory concentration of 4.74 µg/mL. Interestingly, LL37 also binds to ACE2 with an affinity of 25.5 nM and cloaks the ligand-binding domain (LBD), thereby decreasing S1 adherence and protecting cells against pseudovirion infection in vitro. Intranasal administration of LL37 to C57 mice infected with adenovirus expressing human ACE2 either before or after pseudovirion invasion decreased lung infection. The study identified a versatile antimicrobial peptide in humans as an inhibitor of SARS-CoV-2 attachment using dual mechanisms, thus providing a potential candidate for coronavirus disease 2019 (COVID-19) prevention and treatment.

Membrane Nanoparticles Derived from ACE2-Rich Cells Block SARS-CoV-2 Infection.

The ongoing COVID-19 pandemic worldwide necessitates the development of therapeutics against SARS-CoV-2. ACE2 is the main receptor of SARS-CoV-2 S1 and mediates viral entry into host cells. Herein, membrane nanoparticles (NPs) prepared from ACE2-rich cells were discovered to have potent capacity to block SARS-CoV-2 infection. The membranes of human embryonic kidney-239T cells highly expressing ACE2 were applied to prepare NPs using an extrusion method. The nanomaterials, termed ACE2-NPs, contained 265.1 ng mg-1 ACE2 on the surface and acted as baits to trap S1 in a dose-dependent manner, resulting in reduced recruitment of the viral ligand to HK-2 human renal tubular epithelial cells. Aside from affecting receptor recongnition, S1 translocated to the cytoplasm and induced apoptosis by reducing optic atrophy 1 expression and increasing cytochrome c release, which was also inhibited by ACE2-NPs. Further investigations revealed that ACE2-NPs efficiently suppressed SARS-CoV-2 S pseudovirions entry into host cells and blocked viral infection in vitro and in vivo. This study characterizes easy-to-produce memrbane nanoantagonists of SARS-CoV-2 that enrich the existing antiviral arsenal and provide possibilities for COVID-19 treatment.

Inflammasomes and the Maintenance of Hematopoietic Homeostasis: New Perspectives and Opportunities.

Hematopoietic stem cells (HSCs) regularly produce various blood cells throughout life via their self-renewal, proliferation, and differentiation abilities. Most HSCs remain quiescent in the bone marrow (BM) and respond in a timely manner to either physiological or pathological cues, but the underlying mechanisms remain to be further elucidated. In the past few years, accumulating evidence has highlighted an intermediate role of inflammasome activation in hematopoietic maintenance, post-hematopoietic transplantation complications, and senescence. As a cytosolic protein complex, the inflammasome participates in immune responses by generating a caspase cascade and inducing cytokine secretion. This process is generally triggered by signals from purinergic receptors that integrate extracellular stimuli such as the metabolic factor ATP via P2 receptors. Furthermore, targeted modulation/inhibition of specific inflammasomes may help to maintain/restore adequate hematopoietic homeostasis. In this review, we will first summarize the possible relationships between inflammasome activation and homeostasis based on certain interesting phenomena. The cellular and molecular mechanism by which purinergic receptors integrate extracellular cues to activate inflammasomes inside HSCs will then be described. We will also discuss the therapeutic potential of targeting inflammasomes and their components in some diseases through pharmacological or genetic strategies.

Irradiation pretreatment enhances the therapeutic efficacy of platelet-membrane-camouflaged antitumor nanoparticles.

BACKGROUND: Cell membrane-based nanocarriers are promising candidates for delivering antitumor agents. The employment of a simple and feasible method to improve the tumor-targeting abilities of these systems is appealing for further application. Herein, we prepared a platelet membrane (PM)-camouflaged antitumor nanoparticle. The effects of irradiation pretreatment on tumor targeting of the nanomaterial and on its antitumor action were evaluated. RESULTS: The biomimetic nanomaterial constructed by indocyanine green, poly(d,l-lactide-co-glycolide), and PM is termed PINPs@PM. A 4-Gy X-ray irradiation increased the proportions of G2/M phase and Caveolin-1 content in 4T1 breast cancer cells, contributing to an endocytic enhancement of PINPs@PM. PINPs@PM produced hyperthermia and reactive oxygen species upon excitation by near-infrared irradiation, which were detrimental to the cytoplasmic lysosome and resulted in cell death. Irradiation pretreatment thus strengthened the antitumor activity of PINPs@PM in vitro. Mice experiments revealed that irradiation enhanced the tumor targeting capability of PINPs@PM in vivo. When the same dose of PINPs@PM was intravenously administered, irradiated mice had a better outcome than did mice without X-ray pretreatment. CONCLUSION: The study demonstrates an effective strategy combining irradiation pretreatment and PM camouflage to deliver antitumor nanoparticles, which may be instrumental for targeted tumor therapy.

Platelet-membrane-camouflaged bismuth sulfide nanorods for synergistic radio-photothermal therapy against cancer.

Bismuth-containing nanoparticles (BNPs) are potential enhancers for tumor radiotherapy. Improving the bioavailability and developing synergistic therapeutic regimens benefit the drug transformation of BNPs. In the present study, we prepare a mesoporous silica-coated bismuth nanorod (BMSNR) camouflaged by a platelet membrane (PM). This biomimetic material is termed BMSNR@PM. The PM camouflage enhances the immune escape of the BMSNRs by lowering endocytosis by macrophages in the reticuloendothelial system. Additionally, the PM camouflage strengthens the material tumor-targeting capacity and leads to better radiotherapeutic efficacy compared with bare BMSNRs. Owing to the photothermal effect, BMSNR@PMs alters the cell cycle of 4T1 cancer cells post-treatment with 808 nm near-infrared irradiation (NIR). The proportions of S phase and G2/M phase cells decrease and increase, respectively, which explains the synergistic effect of NIR on BMSNR@PM-based radiotherapy. BMSNR@PMs efficiently eradicates cancer cells by the combined action of photothermal therapy (PTT) and radiotherapy in vivo and markedly improves the survival of 4T1-tumor-bearing mice. The synergistic therapeutic effect is superior to the outcomes of PTT and radiotherapy performed alone. Our study demonstrates a versatile bismuth-containing nanoplatform with tumor-targeting, immune escape, and radiosensitizing functionalities using an autologous cell membrane biomimetic concept that may promote the development of radiotherapy enhancers.

Multiscale and Multifunctional Emulsions by Host-Guest Interaction-Mediated Self-Assembly.

Emulsions are widely used in numerous fields. Therefore, there has been increasing interest in the development of new emulsification strategies toward emulsions with advanced functions. Herein we report the formation of diverse emulsions by host-guest interaction-mediated interfacial self-assembly under mild conditions. In this strategy, a hydrophilic diblock copolymer with one block containing ß-cyclodextrin (ß-CD) can assemble at the oil/water interface when its aqueous solution is mixed with an oil phase of benzyl alcohol (BA), by host-guest interactions between ß-CD and BA. This results in significantly reduced interfacial tension and the formation of switchable emulsions with easily tunable droplet sizes. Furthermore, nanoemulsions with excellent stability are successfully prepared simply via vortexing. The self-assembled oil-in-water emulsions also show catastrophic phase inversion, which can generate stable bicontinuous phase and water-in-oil emulsions, thereby further extending phase structures that can be realized by this host-guest self-assembly approach. Moreover, the host-guest nanoemulsions are able to engineer different nanoparticles and microstructures as well as solubilize a diverse array of hydrophobic drugs and dramatically enhance their oral bioavailability. The host-guest self-assembly emulsification is facile, energetically friendly, and fully translatable to industry, therefore representing a conceptually creative approach toward advanced emulsions.

Self-assembly of affinity-controlled nanoparticles via host-guest interactions for drug delivery.

There has been increasing interest in constructing affinity-based drug delivery systems via different non-covalent interactions. Herein we report a host-guest interaction-based strategy to develop effective drug delivery systems using cyclodextrin-containing copolymers. Hydrophilic copolymers with one polyethylene glycol block and another block containing either α-cyclodextrin or ß-cyclodextrin were synthesized. Using poly(ß-benzyl l-aspartate) and pyrene as model guest compounds, we demonstrated the nanoparticle formation by host-guest interaction-mediated self-assembly. When an antioxidant and anti-inflammatory drug Tempol was used, the formation of well-defined spherical nanoparticles and therapeutic loading can be simultaneously realized. The obtained nanotherapy showed affinity-controlled drug release. In vitro cell culture experiments suggested that the host-guest nanotherapy exhibited desirable antioxidant and anti-inflammatory effects in macrophages. In a mouse model of an inflammatory disease ulcerative colitis, the orally administered host-guest nanoparticle can be effectively accumulated in the inflamed colonic tissue. Oral treatment of mice bearing colitis with the nanotherapy led to significantly improved efficacy in comparison with free drugs. A good in vivo safety profile was also observed for the developed host-guest nanotherapy. Accordingly, these types of affinity nanoparticles based on CD-containing copolymers can function as effective nanoplatforms for targeted treatment of a plethora of diseases.

Advanced emulsions via noncovalent interaction-mediated interfacial self-assembly.

We demonstrate that the traditional emulsification theory can be enriched by a self-assembly approach, in which hydrophilic copolymers with one block exhibiting noncovalent forces with the oil phase self-assemble at the oil-water interface, thereby reducing interfacial tension and forming emulsions. This approach was established using affinity diblock copolymers that can interact with oil molecules through electrostatic interactions or hydrogen-bonding. Nanoemulsions with excellent stability were successfully obtained simply via vortexing. The self-assembled emulsions showed unexpected catastrophic phase inversion, further extending the phase structures to bicontinuous and reverse emulsions. Complex emulsions could also be fabricated by this strategy. In addition, the thus prepared nanoemulsions can be used to engineer different nanomaterials.

Yeast Microcapsule-Mediated Targeted Delivery of Diverse Nanoparticles for Imaging and Therapy via the Oral Route.

Targeting of nanoparticles to distant diseased sites after oral delivery remains highly challenging due to the existence of many biological barriers in the gastrointestinal tract. Here we report targeted oral delivery of diverse nanoparticles in multiple disease models, via a "Trojan horse" strategy based on a bioinspired yeast capsule (YC). Diverse charged nanoprobes including quantum dots (QDs), iron oxide nanoparticles (IONPs), and assembled organic fluorescent nanoparticles can be effectively loaded into YC through electrostatic force-driven spontaneous deposition, resulting in different diagnostic YC assemblies. Also, different positive nanotherapies containing an anti-inflammatory drug indomethacin (IND) or an antitumor drug paclitaxel (PTX) are efficiently packaged into YC. YCs containing either nanoprobes or nanotherapies may be rapidly endocytosed by macrophages and maintained in cells for a relatively long period of time. Post oral administration, nanoparticles packaged in YC are first transcytosed by M cells and sequentially endocytosed by macrophages, then transported to neighboring lymphoid tissues, and finally delivered to remote diseased sites of inflammation or tumor in mice or rats, all through the natural route of macrophage activation, recruitment, and deployment. For the examined acute inflammation model, the targeting efficiency of YC-delivered QDs or IONPs is even higher than that of control nanoprobes administered at the same dose via intravenous injection. Assembled IND or PTX nanotherapies orally delivered via YCs exhibit remarkably potentiated efficacies as compared to nanotherapies alone in animal models of inflammation and tumor, which is consistent with the targeting effect and enhanced accumulation of drug molecules at diseased sites. Consequently, through the intricate transportation route, nanoprobes or nanotherapies enveloped in YC can be preferentially delivered to desired targets, affording remarkably improved efficacies for the treatment of multiple diseases associated with inflammation.