Photoreceptor-Mimetic Microflowers for Restoring Light Responses in Degenerative Retina through a 2D Nanopetal/Cell Biointerface.

Retinitis pigmentosa is the main cause of inherited human blindness and is associated with dysfunctional photoreceptors (PRs). Compared with traditional methods, optoelectronic stimulation can better preserve the structural integrity and genetic content of the retina. However, enhancing the spatiotemporal accuracy of stimulation is challenging. Quantum dot-doped ZnIn2S4 microflowers (MF) are utilized to construct a biomimetic photoelectric interface with a 0D/3D heterostructure, aiming to restore the light response in PR-degenerative mice. The MF bio interface has dimensions similar to those of natural PRs and can be distributed within the curved spatial region of the retina, mimicking cellular dispersion. The soft 2D nano petals of the MF provide a large specific surface area for photoelectric activation and simulate the flexibility interfacing between cells. This bio interface can selectively restore the light responses of seven types of retina ganglion cells that encode brightness. The distribution of responsive cells forms a pattern similar to that of normal mice, which may reflect the generation of the initial "neural code" in the degenerative retina. Patch-clamp recordings indicate that the bio interface can induce spiking and postsynaptic currents at the single-neuron level. The results will shed light on the development of a potential bionic subretinal prosthetic toolkit for visual function restoration.

Near-Infrared Photothermally Enhanced Photo-Oxygenation for Inhibition of Amyloid-ß Aggregation Based on RVG-Conjugated Porphyrinic Metal-Organic Framework and Indocyanine Green Nanoplatform.

Amyloid aggregation is associated with many neurodegenerative diseases such as Alzheimer's disease (AD). The current technologies using phototherapy for amyloid inhibition are usually photodynamic approaches based on evidence that reactive oxygen species can inhibit Aß aggregation. Herein, we report a novel combinational photothermally assisted photo-oxygenation treatment based on a nano-platform of the brain-targeting peptide RVG conjugated with the 2D porphyrinic PCN-222 metal-organic framework and indocyanine green (PCN-222@ICG@RVG) with enhanced photo-inhibition in Alzheimer's Aß aggregation. A photothermally assisted photo-oxygenation treatment based on PCN@ICG could largely enhance the photo-inhibition effect on Aß42 aggregation and lead to much lower neurotoxicity upon near-infrared (NIR) irradiation at 808 nm compared with a single modality of photo-treatment in both cell-free and in vitro experiments. Generally, local photothermal heat increases the instability of Aß aggregates and keeps Aß in the status of monomers, which facilitates the photo-oxygenation process of generating oxidized Aß monomers with low aggregation capability. In addition, combined with the brain-targeting peptide RVG, the PCN-222@ICG@RVG nanoprobe shows high permeability of the human blood-brain barrier (BBB) on a human brain-on-a-chip platform. The ex vivo study also demonstrates that NIR-activated PCN-222@ICG@RVG could efficiently dissemble Aß plaques. Our work suggests that the combination of photothermal treatment with photo-oxygenation can synergistically enhance the inhibition of Aß aggregation, which may boost NIR-based combinational phototherapy of AD in the future.

Hybrid theranostic microbubbles for ultrasound/photoacoustic imaging guided starvation/low-temperature photothermal/hypoxia-activated synergistic cancer therapy.

Constructing a theranostic agent for high-contrast multimodality imaging-guided synergistic therapy with long-term tumor retention and minimum systemic side effects still remains a major challenge. Herein, a hybrid microbubble-based theranostic platform was developed for dual-modality ultrasound (US) and enhanced photoacoustic (PA) imaging-guided synergistic tumor therapy by combining starvation therapy, low-temperature photothermal therapy (PTT), and hypoxia-activated therapy, based on polydopamine (PDA) doped poly(vinyl alcohol) microbubbles loaded with glucose oxidase (GOx) (PDA-PVAMBs@GOx) and hypoxia-activated prodrug (HAP) tirapazamine (TPZ). For dual-modality US/enhanced PA imaging, PDA-PVAMBs provided 6.5-fold amplified PA signals relative to freely dispersed PDA nanoparticles (PDA NPs). For synergistic cancer therapy, oxygen (O2) carried by PDA-PVAMBs@GOx was first released to promote starvation therapy by loaded GOx. Then, moderate near-infrared (NIR) laser irradiation triggered PTT and improved enzymatic activity of GOx with its optimal activity around 47 °C. Subsequently, GOx-mediated tumor starvation depleted O2 and exacerbated the hypoxia environment, thereby activating the toxicity of TPZ in the tumor site. Through dual-modality US/PA imaging monitoring, PDA-PVAMBs@GOx with long-term retention (∼7 days) combined with PTT and TPZ significantly inhibited the growth of solid tumors with minimum systemic side effects, which might be a powerful tool for effective tumor treatment.

Dual-Depletion of Intratumoral Lactate and ATP with Radicals Generation for Cascade Metabolic-Chemodynamic Therapy.

Increasing evidence has demonstrated that lactate and adenosine triphosphate (ATP) both play important roles in regulating abnormal metabolism in the tumor microenvironment. Herein, an O2 self-supplying catalytic nanoagent, based on tannic acid (TA)-Fe(III) coordination complexes-coated perfluorooctyl bromide (PFOB) nanodroplets with lactate oxidases (LOX) loading (PFOB@TA-Fe(III)-LOX, PTFL), is designed for cascade metabolic-chemodynamic therapy (CDT) by dual-depletion of lactate and ATP with hydroxyl • OH radicals generation. Benefiting from the catalytic property of loaded LOX and O2 self-supplying of PFOB nanodroplets, PTFL nanoparticles (NPs) efficiently deplete tumoral lactate for down-regulation of vascular endothelial growth factor expression and supplement the insufficient endogenous H2 O2 . Simultaneously, TA-Fe(III) complexes release Fe(III) ions and TA in response to intracellular up-regulated ATP in tumor cells followed by TA-mediated Fe(III)/Fe(II) conversion, leading to the depletion of energy source ATP and the generation of cytotoxic • OH radicals from H2 O2 . Moreover, TA-Fe(III) complexes provide photoacoustic contrast as imaging guidance to enhance therapeutic accuracy. As a result, PTFL NPs efficiently accumulate in tumors for suppression of tumor growth and show evidence of anti-angiogenesis and anti-metastasis effects. This multifunctional nanoagent may provide new insight for targeting abnormal tumor metabolism with the combination of CDT to achieve a synergistic therapeutic effect.

NIR-II-driven and glutathione depletion-enhanced hypoxia-irrelevant free radical nanogenerator for combined cancer therapy.

BACKGROUND: Though the combination of photodynamic therapy (PDT) and chemodynamic therapy (CDT) appears to be very attractive in cancer treatment, hypoxia and overproduced glutathione (GSH) in the tumor microenvironment (TME) limit their efficacy for further application. RESULTS: In this work, a smart hypoxia-irrelevant free radical nanogenerator (AIPH/PDA@CuS/ZIF-8, denoted as APCZ) was synthesized in situ via coating copper sulphide (CuS)-embedded zeolitic imidazolate framework-8 (ZIF-8) on the free radical initiator 2,2'-azobis[2-(2-imidazolin-2-yl)propane]-dihydrochloride (AIPH)-loaded polydopamine (PDA). APCZ showed promising GSH-depleting ability and near-infrared (NIR)-II photothermal performance for combined cancer therapy. Once internalized by 4T1 cells, the outer ZIF-8 was rapidly degraded to trigger the release of CuS nanoparticles (NPs), which could react with local GSH and sequentially hydrogen peroxide (H2O2) to form hydroxyl radical (·OH) for CDT. More importantly, the hyperthermia generated by APCZ upon 1064 nm laser excitation not only permitted NIR-II photothermal therapy (PTT) and promoted CDT, but also triggered the decomposition of AIPH to give toxic alkyl radical (·R) for oxygen-independent PDT. Besides, the PDA together with CuS greatly decreased the GSH level and resulted in significantly enhanced PDT/CDT in both normoxic and hypoxic conditions. The tumors could be completely eradicated after 14 days of treatment due to the prominent therapeutic effects of PTT/PDT/CDT. Additionally, the feasibility of APCZ as a photoacoustic (PA) imaging contrast agent was also demonstrated. CONCLUSIONS: The novel APCZ could realize the cooperative amplification effect of free radicals-based therapies by NIR-II light excitation and GSH consumption, and act as a contrast agent to improve PA imaging, holding tremendous potential for efficient diagnosis and treatment of deep-seated and hypoxic tumors.

Nanoparticle-mediated specific elimination of soft cancer stem cells by targeting low cell stiffness.

As the driving force of tumor progression, cancer stem cells (CSCs) hold much lower cellular stiffness than bulk tumor cells across many cancer types. However, it remains unclear whether low cell stiffness can be harnessed in nanoparticle-based therapeutics for CSC targeting. We report that breast CSCs exhibit much lower stiffness but considerably higher uptake of nitrogen-doped graphene quantum dots (N-GQDs) than bulk tumor cells. Softening/stiffening cells enhances/suppresses nanoparticle uptake through activating/inhibiting clathrin- and caveolae-mediated endocytosis, suggesting that low cell stiffness mediates the elevated uptake in soft CSCs that may lead to the specific elimination. Further, soft CSCs enhance drug release, cellular retention, and nuclear accumulation of drug-loaded N-GQDs by reducing intracellular pH and exocytosis. Remarkably, drug-loaded N-GQDs specifically eliminate soft CSCs both in vitro and in vivo, inhibit tumor but not animal growth, and reduce the tumorigenicity of xenograft cells. Our findings unveil a new mechanism by which low cellular stiffness can be harnessed in nanoparticle-based strategies for specific CSC elimination, opening a new paradigm of cancer mechanomedicine. STATEMENT OF SIGNIFICANCE: Low cell stiffness is associated with high malignancy of tumor cells and thus serves as a mechanical hallmark of CSCs. However, it remains unclear whether cellular stiffness can be exploited for specific targeting of soft CSCs. This work reports that soft CSCs exhibit high N-GQD uptake compared to stiff tumor cells, which is regulated by cellular stiffness. Further, soft CSCs have enhanced drug release, cellular retention, and nuclear accumulation of drug-loaded N-GQDs, which enable the specific elimination of malignant CSCs both in vitro and in vivo with minimal side effect. In summary, our study demonstrates that CSC's low stiffness can be harnessed as a mechanical target for specific eradication, which provides a new paradigm of cancer mechanomedicine.

Nerve Growth Factor-Targeted Molecular Theranostics Based on Molybdenum Disulfide Nanosheet-Coated Gold Nanorods (MoS2-AuNR) for Osteoarthritis Pain.

Osteoarthritis (OA) is a leading cause of chronic pain in the elderly worldwide. Yet current diagnosis and therapy for OA pain are subjective and nonspecific with significant adverse effects. Here, we introduced a theranostic nanoprobe based on molybdenum disulfide nanosheet-coated gold nanorods (MoS2-AuNR) targeting never growth factor (NGF), a key player in pain sensation, for photoacoustic pain imaging and near-infrared (NIR) imaging-guided photothermal analgesic therapy. MoS2 coating significantly improved the photoacoustic and photothermal performance of AuNR. Functionalization of MoS2-AuNR nanoprobes by conjugating with NGF antibody enabled active targeting on painful OA knees in a surgical OA murine model. We observed that our functional nanoprobes accumulated in the OA knee rather than the contralateral intact one, and the amount was correlated with the severity of mechanical allodynia in our mouse model. Under imaging guidance, NIR-excited photothermal therapy could mitigate mechanical allodynia and walking imbalance behavior for both subacute and chronic stages of OA in a preclinical setting. This molecular theranostic approach enabled us to specifically localize the source of OA pain and efficiently block peripheral pain transmission.

Ultra-sensitive photoelectrochemical aptamer biosensor for detecting E. coli O157:H7 based on nonmetallic plasmonic two-dimensional hydrated defective tungsten oxide nanosheets coupling with nitrogen-doped graphene quantum dots (dWO3•H2O@N-GQDs).

Light absorption and interfacial engineering of photoactive materials play vital roles in photoexcited electron generation and electron transport, and ultimately boost the performance of photoelectrochemical (PEC) biosensing. In this work, a novel high-performance photoelectrochemical (PEC) biosensing platform was fabricated based on nonmetallic plasmonic tungsten oxide hydrate nanosheets (WO3•H2O) coupling with nitrogen doped graphene quantum dots (N-GQDs) by a facile one-step hydrothermal approach. The localized surface plasmon resonance (LSPR) properties were achieved by oxygen vacancy engineered WO3·H2O (dWO3•H2O), which could greatly extend the light absorption from visible light to near-infrared light. Moreover, by coupling with N-GQDs, the as-fabricated heterojunction (dWO3•H2O@N-GQD) provided a much enhanced photoelectric response due to the efficient charge transfer. By conjugation with E.coli O157:H7 aptamer, a novel PEC aptasensor based on dWO3•H2O@N-GQD heterojunction was fabricated with a high sensitivity for detection of E.coli O157:H7. The limit of detection (LOD) of this PEC aptasensor is 0.05 CFU/mL with a linear detection range from 0.1 to 104 CFU/mL. Moreover, high reproducibility and good accuracy could also be achieved for analysis in milk samples. This work could provide a promising platform for the development of PEC bioanalysis and offer an insight into the non-metallic plasmonic materials based heterojunctions for high-performances PEC biosensing.

Tannic acid/Mg2+-based versatile coating to manipulate the osteoimmunomodulation of implants.

Instead of directly stimulating osteogenesis, endowing an implant surface with a favourable osteoimmunomodulatory (OIM) function has emerged as a new effective strategy to enhance osteointegration. Though metal-phenolic coatings have demonstrated to possess an immunomodulatory function, their potential application in manipulating an osteoimmune response has not been well explored. Herein, in order to develop a simple, rapid and universal coating method to impart excellent OIM to hard tissue implants, tannic acid (TA) and Mg2+ were selected to form a coating on Ti plate based on metal-phenolic chemistry. Besides its virtues of simplicity, ultrafastness, low-cost, and versatility, another merit for the coating method is that it can easily combine the unique functions of metal ions and phenolic ligands. The chelated Mg2+ can not only activate macrophage polarization towards the anti-inflammatory phenotype but also directly stimulate the osteogenic differentiation of bone marrow-derived stem cells (BMSCs). TA motifs rendered the coating with an excellent reactive oxygen species (ROS) scavenging capacity. TA and Mg2+ showed synergistic effects on regulating macrophage biological behaviour, suppressing its polarization towards the M1 phenotype, and promoting its polarization towards the M2 phenotype. In vivo histological analysis also demonstrated that the TA/Mg2+ coating could effectively inhibit the host response. Finally, the formed osteoimmune environment obviously enhanced the osteogenic differentiation of BMSCs. The above results demonstrated that the designed TA/Mg2+ coating not only possessed the function of directly stimulating osteogenesis but also the function of manipulating OIM to a desired one. Hence, it has great potential to be applied on advanced hard tissue implants to enhance osteointegration.

Porphyrinic Metal-Organic Framework PCN-224 Nanoparticles for Near-Infrared-Induced Attenuation of Aggregation and Neurotoxicity of Alzheimer's Amyloid-ß Peptide.

The aberrant aggregation of amyloid-ß peptide (Aß) in the brain has been considered as the major pathological hallmark of Alzheimer's diseases (AD). Inhibition of Aß aggregation is considered as an attractive therapeutic intervention for alleviating amyloid-associated neurotoxicity. Here, we report the near-infrared light (NIR)-induced suppression of Aß aggregation and reduction of Aß-induced cytotoxicity via porphyrinic metal-organic framework (MOF) PCN-224 nanoparticles. PCN-224 nanoparticles are hydrothermally synthesized by coordinating tetra-kis(4-carboxyphenyl)porphyrin (TCPP) ligands with zirconium. The PCN-224 nanoparticles show high photo-oxygenation efficiency, good biocompatibility, and high stability. The study reveals that the porphyrinic MOF-based nanoprobe activated by NIR light could successfully inhibit self-assembly of monomeric Aß into a ß-sheet-rich structure. Furthermore, photoexcited PCN-224 nanoparticles also significantly reduce Aß-induced cytotoxicity under NIR irradiation.

Isolation and Identification of Rickettsia raoultii in Human Cases: A Surveillance Study in 3 Medical Centers in China.

Background: Rickettsia raoultii is frequently detected in multiple tick species, whereas human infection remains scarcely studied. Methods: A surveillance study was performed at 3 sentinel hospitals in China, to recruit participants with suspected tick exposure. Rickettsia raoultii infection was identified through polymerase chain reaction, followed by sequencing, and confirmed serologically. Isolation by cell culture was performed and the isolates were genome sequenced. Results: Twenty-six subjects were determined to have R. raoultii infection, including 7 with asymptomatic infection, 15 with mild to moderate illness, and 4 with severe illness. Common nonspecific manifestations in the 19 patients with mild to moderate or severe illness included fever (100%), malaise (95%), myalgia (58%), lymphadenopathy (53%), and nausea (42%). Only 5% of them had rash, and 16% had eschar. Scalp eschar and neck lymphadenopathy after a tick bite syndrome was only seen in 2 patients. Of the 4 patients with severe complications, 3 developed pulmonary edema, and 1 developed clouding of consciousness and lethargy. Frequent abnormalities of laboratory testing included leukopenia, thrombocytopenia, lymphopenia, neutropenia, hypoproteinemia, and elevated levels of total bilirubin, hepatic aminotransferases, lactate dehydrogenase, and creatine kinase. All the 19 patients recovered without sequelae after receiving doxycycline treatment. Two R. raoultii strains were isolated, and a significantly less degraded genome was observed than other more virulent Rickettsia strains, indicating a low pathogenicity of the current strain. Conclusions: Human infection with R. raoultii has a wide clinical spectrum that ranged from subclinical infection to severe complications. Physicians need to be aware of the high potential and clinical complexity of R. raoultii infection, to ensure appropriate testing and treatment in endemic regions.

Human Infection with Novel Spotted Fever Group Rickettsia Genotype, China, 2015.

Only 4 species of spotted fever group rickettsiae have been detected in humans in China. However, phylogenetic analysis of samples from 5 ill patients in China indicated infection with a novel spotted fever group Rickettsia, designated Rickettsia sp. XY99. Clinical signs resembled those of severe fever with thrombocytopenia syndrome.

Severe Fever with Thrombocytopenia Syndrome Complicated by Co-infection with Spotted Fever Group Rickettsiae, China.

During 2013-2015 in central China, co-infection with spotted fever group rickettsiae was identified in 77 of 823 patients infected with severe fever with thrombocytopenia syndrome virus. Co-infection resulted in delayed recovery and increased risk for death, prompting clinical practices in the region to consider co-infection in patients with severe fever with thrombocytopenia syndrome.

Candidatus Rickettsia tarasevichiae Infection in Eastern Central China: A Case Series.

BACKGROUND: Human infection with Candidatus Rickettsia tarasevichiae (CRT) was first reported in northeastern China in 2012. OBJECTIVE: To describe the clinical spectrum and laboratory findings of patients infected with CRT in eastern central China. DESIGN: Case series. SETTING: A sentinel hospital for severe fever with thrombocytopenia syndrome (SFTS) in eastern central China in 2014. PARTICIPANTS: Hospitalized patients with SFTS-like illness. MEASUREMENTS: Molecular and serologic tests were performed to diagnose CRT infection. Data about clinical manifestations and laboratory findings were retrieved from medical records. RESULTS: 56 of 733 assessed patients had CRT based on polymerase chain reaction and sequencing. All patients presented with nonspecific manifestations, including fever (96%), malaise (88%), myalgia (57%), cough (25%), and dizziness (14%). Only 2 patients had rash. Further, 16% had eschar, 29% had lymphadenopathy, 100% had gastrointestinal symptoms, 34% had neurologic symptoms, 43% had hemorrhagic manifestations, and 23% had signs of plasma leakage. Thrombocytopenia was observed in 70%, leukopenia in 59%; lymphopenia in 45%; and elevated levels of lactate dehydrogenase in 82%, aspartate aminotransferase in 70%, alanine aminotransferase in 54%, and creatinine kinase in 46%. Co-infection with SFTS virus was documented in 66% patients, and 8 of the 56 patients died. LIMITATIONS: Patients with CRT were not treated for infection because they were retrospectively identified. This was not a population-based study, and the results cannot be generalized to all patients with CRT. CONCLUSION: Candidatus R tarasevichiae infection should be considered in the differential diagnosis of febrile patients with SFTS-like illness in endemic areas. PRIMARY FUNDING SOURCE: National Natural Science Foundation of China.

Common adverse events associated with ribavirin therapy for Severe Fever with Thrombocytopenia Syndrome.

Severe Fever with Thrombocytopenia Syndrome (SFTS) is associated with high mortality rate, for which antiviral therapy with ribavirin was recommended. Based on our previous study, no visible effect of ribavirin therapy in improving clinical outcome was observed. Here we have accumulated the sample size to 634, and by performing prospective observation on the clinical progress and laboratory parameters, we found a significantly higher incidence of anemia and hyperamylasemia in patients who received ribavirin therapy in comparison with those who received no therapy. Generalized estimating equation model disclosed a significant effect on hemoglobin reduction and blood amylase augmentation from ribavirin administration. The occurrence of anemia and hyperamylasemia was associated with SFTS patients receiving ribavirin therapy, which might be adverse event of this drug administration. The recommendation of ribavirin for treating SFTS should be applied with caution.