Covalent Organic Framework-Structured Raman Probes for Ultrasensitive In Vivo Bioimaging.

Organic Raman probes, including polymers and small molecules, have attracted great attention in biomedical imaging owing to their excellent biocompatibility. However, the development of organic Raman probes is usually hindered by a mismatch between their absorption spectra and wavelength-fixed excitation, which makes it difficult to achieve resonance excitation necessary to obtain strong Raman signals. Herein, we introduce a covalent organic framework (COF) into the fine absorption spectrum regulation of organic Raman probes, resulting in their significant Raman signal enhancement. In representative examples, a polymer poly(diketopyrrolopyrrole-p-phenylenediamine) (DPP-PD) and a small molecule azobenzene are transformed into the corresponding COF-structured Raman probes. Their absorption peaks show an accurate match of less than 5 nm with the NIR excitation. As such, the COF-structured Raman probes acquire highly sensitive bioimaging capabilities compared to their precursors with negligible signals. By further mechanism studies, we discover that the crystallinity and size of COFs directly affect the π-conjugation degree of Raman probes, thus changing their bandgaps and absorption spectra. Our study offers a universal and flexible method for improving the signal performance of organic Raman probes without changing their structural units, making it more convenient to obtain the highly sensitive organic Raman probes for in vivo bioimaging.

A DNA-Modularized STING Agonist with Macrophage-Selectivity and Programmability for Enhanced Anti-Tumor Immunotherapy.

The activation of cyclic GMP-AMP (cGAMP) synthase (cGAS) and its adaptor, stimulator of interferon genes (STING), is known to reprogram the immunosuppressive tumor microenvironment for promoting antitumor immunity. To enhance the efficiency of cGAS-STING pathway activation, macrophage-selective uptake, and programmable cytosolic release are crucial for the delivery of STING agonists. However, existing polymer- or lipid-based delivery systems encounter difficulty in integrating multiple functions meanwhile maintaining precise control and simple procedures. Herein, inspired by cGAS being a natural DNA sensor, a modularized DNA nanodevice agonist (DNDA) is designed that enable macrophage-selective uptake and programmable activation of the cGAS-STING pathway through precise self-assembly. The resulting DNA nanodevice acts as both a nanocarrier and agonist. Upon local administration, it demonstrates the ability of macrophage-selective uptake, endosomal escape, and cytosolic release of the cGAS-recognizing DNA segment, leading to robust activation of the cGAS-STING pathway and enhanced antitumor efficacy. Moreover, DNDA elicits a synergistic therapeutic effect when combined with immune checkpoint blockade. The study broadens the application of DNA nanotechnology as an immune stimulator for cGAS-STING activation.

Effect of noninvasive respiratory support after extubation on postoperative pulmonary complications in obese patients: A systematic review and network meta-analysis.

STUDY OBJECTIVE: Obesity is associated with an increased risk of sleep-disordered breathing (SDB) and postoperative pulmonary complications (PPCs). Postoperative noninvasive respiratory support (NRS) has been recommended to obese patients despite the controversy about its benefit. The network meta-analysis (NMA) was used in this study to compare the effect of different methods of NRS on preventing PPCs in obese patients. DESIGN: This study is a network meta-analysis. SETTING: Post-anesthesia care unit and inpatient ward. PATIENTS: 20 randomized controlled trials involving 1184 obese patients were included in the final analysis. INTERVENTIONS: One of the four NRS techniques, which include continuous positive airway pressure (CPAP), bi-level positive airway pressure (BiPAP), high-flow nasal cannula (HFNC), or conventional oxygen therapy (COT), was performed after general anesthesia. MEASUREMENTS: The primary outcome was the incidence of PPCs, e.g., atelectasis, pneumonia, hypoxemia, and respiratory failure. The secondary outcomes included the incidence of oxygen treatment failure and anastomotic leakage, oxygenation index, and length of hospital stay (LOS). RevMan 5.3 and STATA 16.0 were used to analyze the results and any potential bias. MAIN RESULTS: Compared with COT, BiPAP and HFNC were both effective in reducing the occurrence of postoperative atelectasis. There were no significant differences in the occurrence of other PPCs including pneumonia, hypoxemia and respiratory failure between the four NRS techniques. CPAP and HFNC were superior to other techniques in improving oxygenation and shortening LOS respectively. No differences were found in oxygen treatment failure and anastomotic leakage between the patients with different NRS. HFNC ranked the first in five of the eight outcomes (hypoxemia, respiratory failure, treatment failure, anastomotic leakage, LOS) in this review by the surface under the cumulative ranking curve (SUCRA). CONCLUSION: Among the four postoperative NRS techniques, HFNC seems to be the optimal choice for obese patients which shows certain advantages in reducing the risk of PPCs and shortening LOS.

Molecular Planarization of Raman Probes to Avoid Background Interference for High-Precision Intraoperative Imaging of Tumor Micrometastases and Lymph Nodes.

The intraoperative imaging applications of a large number of Raman probes are hampered by the overlap of their signals with the background Raman signals generated by biological tissues. Here, we describe a molecular planarization strategy for adjusting the Raman shift of these Raman probes to avoid interference. Using this strategy, we modify the backbone of thiophene polymer-poly(3-hexylthiophene) (P3HT), and obtain the adjacent thiophene units planarized polycyclopenta[2,1-b;3,4-b']dithiophene (PCPDT). Compared with P3HT whose signal is disturbed by the Raman signal of lipids in tissues, PCPDT exhibits a 60 cm-1 blueshift in its characteristic signal. Therefore, the PCPDT probe successfully avoids the signal of lipids, and achieves intraoperative imaging of lymph nodes and tumor micrometastasis as small as 0.30 × 0.36 mm. In summary, our study presents a concise molecular planarization strategy for regulating the signal shift of Raman probes, and brings a tunable thiophene polymer probe for high-precision intraoperative Raman imaging.

DNA-assembled visible nanodandelions with explosive hydrogen-bond breakage achieving uniform intra-tumor distribution (UITD)-guided photothermal therapy.

Photothermal therapy (PTT) has received increasing attention for treating tumors. However, a long-standing challenge in PTT is non-uniform distribution of photothermal agents (PAs) in tumor tissues, resulting in limited therapeutic efficiency. Herein, inspired by dandelions blowing away by the wind, we have designed a DNA-assembled visible GRS-DNA-CuS nanodandelion, which can achieve uniform intra-tumor distribution (UITD) of PAs, thus enhancing the photothermal therapeutic efficiency. GRS-DNA-CuS is featured by the formation of hydrogen bond between the core of single-strand DNA-modified Raman nanoprobes (GRS) and the shell of complementary single-strand DNA-modified CuS PAs. Under Raman imaging-guided 1st NIR irradiation, hydrogen bond in GRS-DNA-CuS is explosively broken, resulting in large-sized GRS-DNA-CuS (∼135 nm) be completely dissociated into GRS and ultra-small CuS PAs (∼12 nm) within 1 min. Such an explosive dissociation instantly enhances the local concentration of ultra-small CuS PAs and slightly rises intra-tumor temperature, thus increasing the diffusion coefficient of PAs and promoting their UITD. This UITD of CuS PAs enhances the photothermal anti-tumor effects. Three out of five tumors are completely eliminated under photoacoustic imaging-guided 2nd NIR irradiation. Overall, this study provides one UITD-guided PTT strategy for highly effective tumor treatment by exerting explosive breakage property of hydrogen bond, broadening the application scope of DNA-assembly technique in oncology field.

A national descriptive epidemiologic analysis on congenital pulmonary airway malformation in China, 2010-2019.

OBJECTIVE: To depict the epidemiological features of congenital pulmonary airway malformation (CPAM) in Chinese population. METHODS: Using 2010-2019 data from the Chinese Birth Defects Monitoring Network, we calculated the prevalence rates (PR) and 95% confidence intervals of isolated and nonisolated CPAM according to birth year, infant sex, maternal age and residence area, and examined the secular trends by using Poisson regression models. The perinatal outcomes of affected infants and associated malformations with CPAM were also analyzed. RESULTS: During this period, a total of 2451 CPAMs were identified among 20,183,999 births, yielding a PR of 1.21, 0.95, and 0.27 per 10,000 live and still births for the overall, isolated and nonisolated CPAM, respectively. Significant upward trends in CPAM PR were observed. The PR varied significantly by infant sex (male vs. female, 1.28/10,000 vs. 1.10/10,000), residence area (urban vs. rural, 1.49/10,000 vs. 0.88/10,000), and by maternal age (<20 years, 0.94/10,000; 20-24 years, 1.04/10,000; 25-29 years, 1.32/10,000; 30-34 years, 1.28/10,000; ≥35 years, 1.05/10,000). Compared with isolated CPAM, much more live births with nonisolated CPAM died in the early neonatal period (5.0% vs. 1.0%). The additional malformations with nonisolated CPAM occurred most frequently in the circulatory system. CONCLUSIONS: The PR of CPAM in this study are comparable to those reported in non-Chinese populations. The increasing trend in prevalence and poor perinatal outcomes of the affected infants indicate an urgent need to strengthen the clinical and public health interventions of CPAM.

Ultrasensitive Exosome Detection by Modularized SERS Labeling for Postoperative Recurrence Surveillance.

Exosome-based liquid biopsy holds great potential in monitoring tumor progression. Current exosome detection biosensors rely on signal amplification strategies to improve sensitivity; however, these strategies pay little attention to manipulating the number of signal reporters, limiting the rational optimization of the biosensors. Here, we have developed a modularized surface-enhanced Raman spectroscopy (SERS) labeling strategy, where each Raman reporter is coupled with lysine as a signal-lysine module, and thus the number of Raman reporters can be precisely controlled by the modularized solid-phase peptide synthesis. Using this strategy, we screened out an optimum Raman biosensor for ultrasensitive exosome detection, with the limit of detection of 2.4 particles per microliter. This biosensor enables a successful detection of the tumor with an average diameter of approximately 3.55 mm, and thus enables successful surveillance of the postoperative tumor recurrence in mice models and distinguishing cancer patients from healthy subjects. Our work provides a de novo strategy to precisely amplify signals toward a myriad of biosensor-related medical applications.

tLyP-1 Peptide Functionalized Human H Chain Ferritin for Targeted Delivery of Paclitaxel.

PURPOSE: The aims of this study were to test the feasibility, targeting specificity and anticancer therapeutic efficacy of CendR motif tLyP-1 functionalized at the N-terminal of ferritin for paclitaxel (PTX) delivery. METHODS: A tumor homing and penetrating peptide tLyP-1 was fused to the N-terminal of human H chain ferritin (HFtn) to generate a dual-targeting nanoparticle delivery system. PTX molecules were encapsulated into the HFtn nanocage using the disassembly/assembly method by adjusting pHs. Cellular uptake was examined by confocal laser scanning microscopy (CLSM) and flow cytometry. The MTT assay was used to test the cytotoxicity of various PTX-loaded NPs against MDA-MB-231 and SMMC-7721 tumor cells. The wound healing and cell migration assays were conducted to assess the inhibitory effect on cell motility and metastasis. The inhibition effect on the SMMC-7721 tumor spheroids was studied and penetration ability was evaluated by CLSM. The antitumor efficacy of PTX-loaded NPs was assessed in MDA-MB-231 breast cancer xenografted in female BALB/c nude mice. RESULTS: Compared with HFtn-PTX, in vitro studies demonstrated that the tLyP-1-HFtn-PTX displayed enhanced intracellular delivery and better cytotoxicity and anti-invasion ability against both SMMC-7721 and MDA-MB-231 cells. The better penetrability and growth inhibitory effect on SMMC-7721 tumor spheroids were also testified. In vivo distribution and imaging demonstrated that the tLyP-1-HFtn-PTX NPs were selectively accumulated and penetrated at the tumor regions. Verified by the breast cancer cells model in BABL/c nude mice, tLyP-1-HFtn-PTX displayed higher in vivo therapeutic efficacy with lower systemic toxicity. CONCLUSION: Ferritin decorated with tumor-homing penetration peptide tLyP-1 at the N terminal could deliver PTX specifically inside the cell via receptor-mediated endocytosis with better efficacy. The peptide tLyP-1 which is supposed to work only at the C terminus showed enhanced tumor tissue penetration and antitumor efficacy, demonstrating that it also worked at the N-terminal of HFtn.

Novel Paclitaxel-Loaded Nanoparticles Based on Human H Chain Ferritin for Tumor-Targeted Delivery.

Paclitaxel (PTX), an excellent chemotherapeutic antitumor drug, is widely used to treat patients with various cancers. However, its clinical applications are greatly restricted by poor solubility and lack of targeting. Herein, we applied natural human H chain ferritin (HFtn) nanocages that can bind to tumor cells via interacting with the human transferritin receptor 1 (TfR1) leading to its endocytosis as the PTX carrier for the targeted delivery. PTX molecules were encapsulated into HFtn cavity using disassembly/reassembly method through adjusting pH. According to the requirements of drugs suitable for clinical trials, HFtn can be easily purified in high yields with no ligand modification or property modulation. We demonstrated that PTX molecules were successfully encapsulated in the protein nanocages. The HFtn-PTX nanoparticles exhibited similar morphology and structural characteristics to the hollow cage and showed significant cytotoxicity in vitro than the naked PTX. Flow cytometry, confocal laser scanning microscopy, and in vivo imaging of MDA-MB-231 tumor demonstrated the HFtn-PTX nanoparticles targeting ability to tumor cells. Cell apoptosis assay showed that HFtn-PTX had similar apoptotic characteristics on MDA-MB-231 cells as that of the free PTX. HFtn-PTX nanoparticles have higher in vivo therapeutic efficacy and lower systemic toxicity. The BALB/c mice model also confirmed the effectiveness of the nanoparticles. Specifically targeting to tumors and solving the solubility issue of water-insoluble drugs thus alleviating the side effects, HFtn can be an efficient hydrophobic drug delivery nanocarrier for further applications in cancer therapy.

Exact comprehensive equations for the photon management properties of silicon nanowire.

Unique photon management (PM) properties of silicon nanowire (SiNW) make it an attractive building block for a host of nanowire photonic devices including photodetectors, chemical and gas sensors, waveguides, optical switches, solar cells, and lasers. However, the lack of efficient equations for the quantitative estimation of the SiNW's PM properties limits the rational design of such devices. Herein, we establish comprehensive equations to evaluate several important performance features for the PM properties of SiNW, based on theoretical simulations. Firstly, the relationships between the resonant wavelengths (RW), where SiNW can harvest light most effectively, and the size of SiNW are formulized. Then, equations for the light-harvesting efficiency at RW, which determines the single-frequency performance limit of SiNW-based photonic devices, are established. Finally, equations for the light-harvesting efficiency of SiNW in full-spectrum, which are of great significance in photovoltaics, are established. Furthermore, using these equations, we have derived four extra formulas to estimate the optimal size of SiNW in light-harvesting. These equations can reproduce majority of the reported experimental and theoretical results with only ~5% error deviations. Our study fills up a gap in quantitatively predicting the SiNW's PM properties, which will contribute significantly to its practical applications.

A comparison of light-harvesting performance of silicon nanocones and nanowires for radial-junction solar cells.

Silicon nanorod based radial-junction solar cells are competitive alternatives to traditional planar silicon solar cells. In various silicon nanorods, nanocone is always considered to be better than nanowire in light-absorption. Nevertheless, we find that this notion isn't absolutely correct. Silicon nanocone is indeed significantly superior over nanowire in light-concentration due to its continuous diameters, and thus resonant wavelengths excited. However, the concentrated light can't be effectively absorbed and converted to photogenerated carriers, since its propagation path in silicon nanocone is shorter than that in nanowire. The results provide critical clues for the design of silicon nanorod based radial-junction solar cells.