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Abiotic organic chemistry reactions typically occur outside of biological context. This review describes the mechanisms and examples for harnessing abiotic organic chemistry in living systems and highlights the relevant biomedical applications.

Diabetic wound healing is one of the major challenges in the biomedical fields. The conventional single drug treatments have unsatisfactory efficacy, and the drug delivery effectiveness is restricted by the penetration depth. Herein, we develop a magnesium organic framework-based microneedle patch (denoted as MN-MOF-GO-Ag) that can realize transdermal delivery and combination therapy for diabetic wound healing. Multifunctional magnesium organic frameworks (Mg-MOFs) are mixed with poly(γ-glutamic acid) (γ-PGA) hydrogel and loaded into the tips of MN-MOF-GO-Ag, which slowly releases Mgsup2+/supand gallic acid in the deep layer of the dermis. The released Mgsup2+/supinduces cell migration and endothelial tubulogenesis, while gallic acid, a reactive oxygen species-scavenger, promotes antioxidation. Besides, the backing layer of MN-MOF-GO-Ag is made of γ-PGA hydrogel and graphene oxide-silver nanocomposites (GO-Ag) which further enables excellent antibacterial effects for accelerating wound healing. The therapeutic effects of MN-MOF-GO-Ag on wound healing are demonstrated with the full-thickness cutaneous wounds of a diabetic mouse model. The significant improvement of wound healing is achieved for mice treated with MN-MOF-GO-Ag.

Background Acute kidney injury (AKI) with high mortality rates is associated with an excess of reactive oxygen/nitrogen species (RONS) within kidney tissues. Recently, nanomedicine antioxidant therapy has been used to alleviate AKI. Herein, we synthesized ultrasmall Prussian blue nanozymes (PB NZs, 4.5 nm) as theranostic agents for magnetic resonance (MR)/photoacoustic (PA) dual-modal imaging guided AKI treatment. Results PB NZs exhibited multi-enzyme mimetic abilities, promoting the effective elimination of RONS both in vitro and in vivo. Moreover, benefiting from their imaging contrast properties, the rapid renal accumulation of PB NZs was verified by in vivo PA/MR dual-modal imaging. Due to their excellent enrichment in the kidney and unique multi-enzyme mimetic abilities, ultrasmall PB NZs displayed superior AKI treatment efficacy compared with that of amifostine in two clinically relevant types of AKI induced murine models (either by rhabdomyolysis or cisplatin). Conclusion Our findings suggested ultrasmall PB NZs, as nanozyme theranostics, have great potential for AKI management. Graphic abstract

Toward non-genetic non-invasive neural modulation with a submillimeter precision, we report the development and application of photoacoustic nanotransducers (PAN) to neural stimulation in cultured primary neurons and in live brain. Our PAN, based on synthesized semiconducting polymer nanoparticles, efficiently generate localized ultrasound by a photoacoustic process upon absorption of nanosecond pulsed light in the NIR-II window. We showed that PAN binding on the neuron membrane through non-specific interaction and specific targeting of mechanosensitive ion channels both successfully activate primary neurons in culture. We also demonstrated in live mouse brain motor cortex activation and invoked subsequent motor responses through PAN.

Photoacoustic (PA) probes absorbing in the second near-infrared (NIR-II: 1000-1700 nm) window hold great promise for deep-tissue diagnosis and treatment. Currently, NIR-II PA probes typically involve complex synthesis and surfactant adjuvant for processing and delivery. Furthermore, these NIR-II PA probes are "always-on," leading to inadequate signal-to-background ratio and low specificity. To address these challenges, this study reports a pH-activatable and aggregation-enhanced NIR-II PA probe. Without using any toxic or exotic oxidants, the selected polymer (PPE) is readily doped by oxygen in an ambient environment and simultaneously red-shifts its absorption profile from visible to NIR-II region. By virtue of the carboxyl groups on the side chains, oxygen-doped PPE is readily water-soluble at a physiological pH but tends to aggregate in an acidic environment. The pH-induced aggregation results in a significant PA enhancement and thus allows specific PA imaging of acidic tumor microenvironment in vivo. Our study provides a facile and surfactant-free strategy for achieving water-soluble and pH-responsive NIR-II PA probes, which could be applied for diagnoses of cancer and other diseases associated with changes in pH. It paves the way for the development of new activatable NIR-II imaging probes and also could facilitate the investigation of biological and pathological processes in deep tissue.

Scn2a encodes voltage-gated sodium channel NaV1.2, which mediates neuronal firing. The current paradigm suggests that NaV1.2 gain-of-function variants enhance neuronal excitability resulting in epilepsy, whereas NaV1.2 deficiency impairs neuronal excitability contributing to autism. In this paradigm, however, why about a third of patients with NaV1.2 deficiency still develop seizures remains a mystery. Here we challenge the conventional wisdom, reporting that neuronal excitability is increased with severe NaV1.2 deficiency. Using a unique gene-trap knockout mouse model of Scn2a, we found enhanced intrinsic excitabilities of principal neurons in the cortico-striatal circuit, known to be involved in Scn2a-related seizures. This increased excitability is autonomous, and is reversible by genetic restoration of Scn2a expression in adult mice. Mechanistic investigation reveals a compensatory downregulation of potassium channels including KV1.1, which could be targeted to alleviate neuronal hyperexcitability. Our unexpected findings may explain NaV1.2 deficiency-related epileptic seizures in humans and provide molecular targets for potential interventions.TEASERSevere NaV1.2 deficiency results in neuronal hyperexcitability via the compensatory downregulation of potassium channels.HIGHLIGHTSSevere NaV1.2 deficiency results in enhanced excitability of medium spiny neurons (MSNs) and pyramidal neurons in adult mice;Increased neuronal excitability in MSNs is accompanied by elevated voltage threshold;NaV1.2 deficiency-related hyperexcitability is reversible with the restoration of Scn2a expression, and is autonomous;The expression of the KV1.1 channel has a compensatory reduction in neurons with NaV1.2 deficiency, and KV channels openers normalize the neuronal excitability;The enhanced excitability in brain slices translates to elevated in vivo firing commonly associated with seizures.

Enzyme therapeutics have received increasing attention due to their high biological specificity, outstanding catalytic efficiency, and impressive therapeutic outcomes. Protecting and delivering enzymes into target cells while retaining enzyme catalytic efficiency is a big challenge. Wrapping of enzymes with rational designed polymer shells, rather than trapping them into large nanoparticles such as liposomes, have been widely explored because they can protect the folded state of the enzyme and make post-functionalization easier. In this review, the methods for wrapping up enzymes with protective polymer shells are mainly focused on. It is aimed to provide a toolbox for the rational design of polymeric enzymes by introducing methods for the preparation of polymeric enzymes including physical adsorption and chemical conjugation with specific examples of these conjugates/hybrid applications. Finally, a conclusion is drawn and key points are emphasized.

Nanotheranostic agents of gold nanomaterials in the second near-infrared (NIR-II) window have attracted significant attention in cancer management, owing to the reduced background signal and deeper penetration depth in tissues. However, it is still challenging to modulate the localized surface plasmon resonance (LSPR) of gold nanomaterials from the first near-infrared (NIR-I) to NIR-II region. Herein, a plasmonic modulation strategy of gold nanorods (GNRs) through manganese dioxide coating is developed for NIR-II photoacoustic/magnetic resonance (MR) duplex-imaging-guided NIR-II photothermal chemodynamic therapy. GNRs are coated with silica dioxide (SiO2 ) and then covered with magnesium dioxide (MnO2 ) to obtain the final product of GNR@SiO2 @MnO2 (denoted as GSM). The LSPR peak of GNRs could be tuned by adjusting the thickness of the MnO2 layer. Theoretical simulations reveal that this plasmonic modulation is mainly due to the change of refraction index around the GNRs after coating with the MnO2 layer. Additionally, the MnO2 layer is demonstrated to degrade into Mn2+ ions in response to peroxide and acidic protons in the tumor microenvironment, which allows for MR imaging and chemodynamic therapy. This plasmonic modulation strategy can be adapted to other metal nanomaterials and the construction of a new class of NIR-II nanotheranostics.

Companion diagnostics (CDx) provides critical information for precision medicine. However, current CDx is mostly limited to in vitro tests, which cannot accurately evaluate the disease progression and treatment response in real time. To overcome this challenge, herein a glucose oxidase (GOx)-engineered conjugated polymer (polyaniline, PANI) nanoplatform (denoted as PANITG) is reported for activatable imaging-based CDx and multistage augmented photothermal/starvation synergistic therapy. PANITG comprises a pH-activatable conjugated polymer as a photothermal convertor and photoacoustic (PA) emitter, a GOx as a cancer starvation inducer as well as a H

Neuromodulation is an invaluable approach for study of neural circuits and clinical treatment of neurological diseases. Here, we report semiconducting polymer nanoparticles based photoacoustic nanotransducers (PANs) for neural stimulation. Our PANs strongly absorb light in the near-infrared second window and generate localized acoustic waves. PANs can also be surface-modified to selectively bind onto neurons. PAN-mediated activation of primary neurons in vitro is achieved with ten 3-nanosecond laser pulses at 1030 nm over a 3 millisecond duration. In vivo neural modulation of mouse brain activities and motor activities is demonstrated by PANs directly injected into brain cortex. With millisecond-scale temporal resolution, sub-millimeter spatial resolution and negligible heat deposition, PAN stimulation is a new non-genetic method for precise control of neuronal activities, opening potentials in non-invasive brain modulation.

Molecular imaging revolutionized the way researchers and clinicians visualize and investigate complex biochemical phenomena, and it is beneficial for disease diagnosis, drug design and therapy assessment. Among a variety of different imaging techniques, the non-ionizing and non-invasive photoacoustic (PA) imaging is attracting increased attentions, owing to its high spatial and temporal resolutions with reasonable penetration depth in tissue. Parallel efforts have been the preparation of PA imaging agents which has high PA efficacy and can specifically label the targets at cellular or molecular level. Particularly, there is exponentially growing interest in imaging in the second near-infrared (NIR-II) window (1000–1700 nm), where offers reduced tissue background and improved penetration depth. However, study of PA imaging in the NIR-II window is incomplete, partly due to the lack of suitable materials. Therefore, in my dissertation work I studied NIR-II PA imaging through semiconducting polymer. Firstly, the performance of PA imaging in the NIR-II window is explored by using a semiconducting polymer nanoparticle (SPN) which has strong absorption in the NIR-II window. Compared with lipid, blood and water, such SPN shows outstanding PA contrast in the NIR-II window in situ and in vivo, and an imaging depth of more than 5 cm at 1064 nm excitation is achieved in chicken-breast tissue. These results suggest that SPN as a PA contrast in the NIR-II window opens new opportunities for biomedical imaging with improved imaging contrast and centimeter-deep imaging depth. Next, targeted PA imaging of prostate cancer is achieved by functionalizing a NIR-II absorbing SPN with prostate-specific membrane antigen (PSMA)-targeted ligands. Insights into the interaction of the imaging probes with the biological targets are obtained from single-cell to whole-organ by transient absorption (TA) microscopy and PA imaging. TA microscopy reveals the targeting efficiency, kinetics, and specificity of the functionalized SPN to PSMA-positive prostate cancer at cellular level. Meanwhile, the functionalized SPN demonstrates selective accumulation and retention in the PSMA-positive tumor after intravenous administration in vivo. Taken together, it is demonstrated that BTII-DUPA SPN is a promising targeted probe for prostate cancer diagnosis by PA imaging. Lastly, PA imaging in the NIR-II window is also achieved water-soluble semiconducting polymer, which is prepared by oxygen-doping. After doping, it shows broadband absorption in the entire NIR-II window, with great chemical stability, photostability and biocompatibility. Owing to its merit of broadband absorption, the imaging depth comparison among different NIR-II wavelengths is also achieved. Moreover, this doped semiconducting polymer is readily soluble in normal physiological pH by virtue of carboxyl groups on side chains and tends to aggregate at an acidic environment which results in a 7.6-fold PA enhancement at pH 5.0. Importantly, a 3.4±1.0-fold greater signal in tumor tissue than that in muscle is revealed in vivo. This study provides a more attainable yet effective platform to the field for achieving water-soluble NIR-II absorbing contrast agents for activatable PA imaging.

Development of specific molecular probes holds great promise for early diagnosis of aggressive prostate cancer (PCa). Here, 2-[3-(1,3-dicarboxypropyl) ureido] pentanedioic acid (DUPA)-conjugated ligand and bis-isoindigo-based polymer (BTII) are synthesized to formulate semiconducting polymer nanoparticles (BTII-DUPA SPN) as a prostate-specific membrane antigen (PSMA)-targeted probe for PCa imaging in the NIR-II window. Insights into the interaction of the imaging probes with the biological targets from single-cell to whole-organ levels are obtained by transient absorption microscopy (TAM) and photoacoustic tomography (PAT). The targeting mechanism, kinetics, and specificity of BTII-DUPA SPN to PSMA-positive PCa cells are revealed at cellular level with TAM. At the organ level, PAT imaging of BTII-DUPA SPN in the NIR-II window demonstrates superior penetration depth and imaging contrast. By intravenous administration, BTII-DUPA SPN demonstrates selective accumulation and retention in the PSMA-positive tumor, allowing noninvasive PAT detection of PSMA overexpressing PCa. The distribution of nanoparticles at tissue level is further analyzed through TAM. These results collectively demonstrate a new SPN for targeted cancer detection by TAM and PAT imaging.

Three types of macroanion-countercation interactions in dilute solution, decided by the strength of electrostatic attraction and the change of hydration shells are reported: minor interaction between macroanions [MO8 Pd12 (SeO3 )8 ]6- (M=Zn2+ or Ni2+ ) and monovalent cations (Na+ , K+ , Rb+ , Cs+ ), leaving their hydration shells intact (solvent-separated ion-pairs); strong binding between macroanions and divalent cations (Sr2+ , Ba2+ ) to form solvent-shared ion-pairs with partial dehydration; very strong electrostatic attraction between macroanions and Y3+ ion with contact ion-pairs formation by severely breaking their original hydration shells and forming new ones. In addition, divalent cations can help the macroanions self-assemble into hollow spherical blackberry structures through counterion-mediated attraction, whereas macroanions with mono- or trivalent cations only stay as discrete ions due to either weak interaction or a small number of bound countercations.

A 3D printed enzyme‐functionalized scaffold based on glucose oxidase (GOx) and catalase (CAT)‐assisted biomineralized calcium phosphate (CaP) nanosheets (CaP@CAT NSs) is prepared. The hyperglycemia and inflammation environment can be alleviated by the catalysis of GOx and CaP@CAT NSs. Meanwhile, the initiated hypoxia can stimulate angiogenesis and the degraded Ca2+ and PO43− ions can enhance osteogenesis, thus facilitating diabetic bone regeneration.

The electrochromism of a water-soluble naturally oxidized electrochromic polymer, ox-PPE, is harnessed for rapid and facile bacterial detection, discrimination, and susceptibility testing. The ox-PPE solution shows distinct colorimetric and spectroscopic changes within 30 min when mixed with live bacteria. For the underlying mechanism, it is found that ox-PPE responds to the reducing species (e.g. cysteine and glutathione) released by metabolically active bacteria. This reduction reaction is ubiquitous among various bacterial strains, with a noticeable difference that enables discrimination of Gram-negative and Gram-positive bacterial strains. Combining ox-PPE with antibiotics, methicillin-susceptible and -resistant S. aureus can be differentiated within 2.5 h. Proof-of-concept demonstration of ox-PPE for antimicrobial susceptibility testing is carried out by incubating E. coli with various antibiotics. The obtained minimum inhibition concentrations are consistent with the conventional culture-based methods, but with the procedure time significantly shortened to 3 h.

Fullerene molecule covalently functionalized with 12 carboxylic acid groups on its periphery was synthesized, and its solution behavior was explored. The functionalized fullerene molecules behave as hydrophilic macroions in polar solvents by showing strong attractions with each other mediated from their counterions and consequently self-assembling into single-layer, hollow, spherical blackberry-type structures in solvents with moderate polarity. The fullerene molecules are not touching with each other in the assemblies, and the assembly size can be tuned by changing the polarity of the solvents. More importantly, the transition between the self-assembly and the disassembly of the macroions can be easily achieved by changing temperature. The discovery confirms that the semirigid clusters demonstrate the unique solution behavior of macroions and open up a new way to assemble fullerene into functional materials and devices.

International audience; The Cosmic Ray Energetics And Mass experiment for the International Space Station (ISS-CREAM) is a space-borne mission designed for the precision measurement of the energy and elemental composition of cosmic rays. It is scheduled to be launched and installed on the ISS in August 2017. The Silicon Charge Detector (SCD), placed at the top of the ISS-CREAM payload, consists of 4 layers. Each layer has 2688 silicon pixels and associated electronics arranged in such a fashion that its active detection area of 78 x 74 cm2 is free of any dead area. The foremost goal of the SCD is to efficiently and precisely measure the charge of cosmic rays passing through it. The 4-layer configuration was chosen to achieve the best precision in measuring the charge of cosmic rays within the constraints on the mass, volume and power allotted to it. The amount of material used for its support structure was minimized as well to reduce the chance of interactions of the cosmic ray within the structure. Given the placement of the SCD, its 4-layer configuration and the minimal amount of material in the cosmic-ray trajectory, the SCD is designed to measure the charge of cosmic rays ranging from protons to iron nuclei with excellent detection efficiency and charge resolution. We present the design and fabrication of the SCD. It successfully underwent space environment tests including vibration and thermal-vacuum qualification. We present the performance of the SCD during these tests, as well as its charge-measurement performance on the ground using cosmic muons and heavy ions in CERN beam tests.

Breast-conserving surgery is a well-accepted breast cancer treatment. However, it is still challenging for the surgeon to accurately localize the tumor during the surgery. Also, the guidance provided by current methods is 1 dimensional distance information, which is indirect and not intuitive. Therefore, it creates problems on a large re-excision rate, and a prolonged surgical time. To solve these problems, we have developed a fiber-delivered optoacoustic guide (OG), which mimics the traditional localization guide wire and is preoperatively placed into tumor mass, and an augmented reality (AR) system to provide real-time visualization on the location of the tumor with sub-millimeter variance. By a nano-composite light diffusion sphere and light absorbing layer formed on the tip of an optical fiber, the OG creates an omnidirectional acoustic source inside tumor mass under pulsed laser excitation. The optoacoustic signal generated has a high dynamic range (~ 58dB) and spreads in a large apex angle of 320 degrees. Then, an acoustic radar with three ultrasound transducers is attached to the breast skin, and triangulates the location of the OG tip. With an AR system to sense the location of the acoustic radar, the relative position of the OG tip inside the tumor to the AR display is calculated and rendered. This provides direct visual feedback of the tumor location to surgeons, which will greatly ease the surgical planning during the operation and save surgical time. A proof-of-concept experiment using a tablet and a stereo-vision camera is demonstrated and 0.25 mm tracking variance is achieved.

A molecular photochromic spiropyran-polyoxometalate-alkyl organic-inorganic hybrid has been synthesized and fully characterized. The reversible switching of the hydrophobic spiropyran fragment to the hydrophilic merocyanine one can be easily achieved under light irradiation at different wavelengths. This switch changes the amphiphilic feature of the hybrid, leading to a light-controlled self-assembly behavior in solution. It has been shown that the hybrid can reversibly self-assemble into vesicles in polar solvents and irreversibly into reverse vesicles in non-polar solvents. The sizes of the vesicles and the reverse vesicles are both tunable by the polarity of the solvent, with the hydrophobic interactions being the main driving force.

Thienoisoindigo-based semiconducting polymer with a strong near-infrared absorbance is synthesized and its water-dispersed nanoparticles (TSPNs) are investigated as a contrast agent for photoacoustic (PA) imaging in the second near-infrared (NIR-II) window (1000-1350 nm). The TSPNs generate a strong PA signal in the NIR-II optical window, where background signals from endogenous contrast agents, including blood and lipid, are at the local minima. By embedding a TSPN-containing tube in chicken-breast tissue, an imaging depth of more than 5 cm at 1064 nm excitation is achieved with a contrast-agent concentration as low as 40 µg mL-1 . The TSPNs under the skin or in the tumor are clearly visualized at 1100 and 1300 nm, with negligible interference from the tissue background. TSPN as a PA contrast in the NIR-II window opens new opportunities for biomedical imaging of deep tissues with improved contrast.