Homotypic Membrane-Enhanced Blood-Brain Barrier Crossing and Glioblastoma Targeting for Precise Surgical Resection and Photothermal Therapy.

The crossing of blood-brain barrier (BBB) is essential for glioblastoma (GBM) therapy, and homotypic targeting is an effective strategy to achieve BBB crossing. In this work, GBM patient-derived tumor cell membrane (GBM-PDTCM) is prepared to cloak gold nanorods (AuNRs). Relying on the high homology of the GBM-PDTCM to the brain cell membrane, GBM-PDTCM@AuNRs realize efficient BBB crossing and selective GBM targeting. Meanwhile, owing to the functionalization of Raman reporter and lipophilic fluorophore, GBM-PDTCM@AuNRs are able to generate fluorescence and Raman signals at GBM lesion, and almost all tumor can be precisely resected in 15 min by the guidance of dual signals, ameliorating the surgical treatment for advanced GBM. In addition, photothermal therapy for orthotopic xenograft mice is accomplished by intravenous injection of GBM-PDTCM@AuNRs, doubling the median survival time of the mice, which improves the nonsurgical treatment for early GBM. Therefore, benefiting from homotypic membrane-enhanced BBB crossing and GBM targeting, all-stage GBM can be treated with GBM-PDTCM@AuNRs in distinct ways, providing an alternative idea for the therapy of tumor in the brain.

A simple and sensitive electrochemical biosensor for circulating tumor cell determination based on dual-toehold accelerated catalytic hairpin assembly.

Tumor cells in blood circulation (CTCs) are vital biomarkers for noninvasive cancer diagnosis. We developed a simple and sensitive electrochemical biosensor based on dual-toehold accelerated catalytic hairpin assembly (DCHA) to distinguish CTCs from blood cells. In the presence of CTCs, the aptamer probe initiates the DCHA process, which produces amplified electrochemical signals. Compared with conventional catalytic hairpin assembly (CHA), the proposed DCHA showed high sensitivity, which led to a broader working range of 10-1000 cells mL-1 with a limit of detection of 4 cells mL-1. Furthermore, our method exhibited an excellent capability of distinguishing malignant breast cancers from healthy people, with a sensitivity of 97.4%. In summary, we have established an enzyme-free, easy-to-operate, and nondisruptive method for detecting circulating tumor cells in blood circulation based on the DCHA strategy. Its versatility and simplicity will make it more widely used in clinical diagnosis and biomedical research.

Stereotactic Photodynamic Therapy Using a Two-Photon AIE Photosensitizer.

Two-photon photodynamic therapy (TP-PDT) is emerging as a powerful strategy for stereotactic targeting of diseased areas, but ideal photosensitizers (PSs) are currently lacking. This work reports a smart PS with aggregation-induced emission (AIE) feature, namely DPASP, for TP-PDT with excellent performances. DPASP exhibits high affinity to mitochondria, superior photostability, large two-photon absorption cross section as well as efficient reactive oxygen species generation, enabling it to achieve photosensitization both in vitro and in vivo under two-photon excitation. Moreover, its capability of stereotactic ablation of targeted cells with high-precision is also successfully demonstrated. All these merits make DPASP a promising TP-PDT candidate for accurate ablation of abnormal tissues with minimal damages to surrounding areas in the treatment of various diseases.

Optical Fiber-Enabled In Situ Photocatalytic Hydrogen Generation for Infiltrating Tumor Therapy in Brain.

In addition to repressing proliferation, inhibiting the infiltration of tumor cells is an important strategy to improve the treatment of malignant tumors. Herein, a photocatalyst (pCNMC@Pt) is designed by sequentially assembling manganese dioxide, chlorin e6, and platinum (Pt) nanoparticles onto protonated graphitic carbon nitride. With the help of a Z-scheme structure and near-infrared (NIR) photosensitizer, pCNMC@Pt is capable of responding to NIR light to generate large amounts of hydrogen (H2). Taking lactic acid in the tumor microenvironment as a sacrificial reagent, H2 therapy initiated by the NIR photocatalyst remarkably impedes the growth of glioblastoma (GBM). More importantly, it is found that H2 can suppress the stemness of glioma stem cells, curbing both proliferation and infiltration of GBM. Furthermore, since pCNMC@Pt and light source are precisely co-localized through a self-built loading and illumination system, GBM in mouse brains can be efficiently treated, providing an alternative gas therapy approach to cure infiltrating tumors.

A Blood-Responsive AIE Bioprobe for the Ultrasensitive Detection and Assessment of Subarachnoid Hemorrhage.

Subarachnoid hemorrhage (SAH) is a severe subtype of stroke caused by the rupturing of blood vessels in the brain. The ability to accurately assess the degree of bleeding in an SAH model is crucial for understanding the brain-damage mechanisms and developing therapeutic strategies. However, current methods are unable to monitor microbleeding owing to their limited sensitivities. Herein, a new bleeding assessment system using a bioprobe TTVP with aggregation-induced emission (AIE) characteristics is demonstrated. TTVP is a water-soluble, small-molecule probe that specifically interacts with blood. Taking advantage of its AIE characteristics, cell membranes affinity, and albumin-targeting ability, TTVP fluoresces in bleeding areas and detects the presence of blood with a high signal-to-noise (S/N) ratio. The degree of SAH bleeding in an endovascular perforation model is clearly evaluated based on the intensity of the fluorescence observed in the brain, which enables the ultrasensitive detection of mirco-bleeding in the SAH model in a manner that outperforms the current imaging strategies. This method serves as a promising tool for the sensitive analysis of the degree of bleeding in SAHs and other hemorrhagic diseases.

Tetrahedral framework nucleic acids linked CRISPR/Cas13a signal amplification system for rare tumor cell detection.

The sensitive and accurate detection of rare tumor cells provides precise diagnosis and dynamic assessment information in various tumor spectrums. However, rare tumor cells assay is still a challenge due to the exceedingly rare presence in the blood. In this research, we develop a fluorescent approach for the identification of rare tumor cells based on a combination of immunosorbent capture and a three-step signal amplification strategy. First, rare tumor cells are captured by immunoadsorption on 96-well plates. Second, self-synthesized tetrahedral framework nucleic acids (tFNAs) spontaneously anchor into the lipid bilayer of rare tumor cells, resulting in a "one to more" amplification effect. Then, the double-stranded DNA (dsDNA) binds to the vertices of the tFNAs and generates a large amount of target RNA by T7 polymerase, which is the secondary signal amplification. Finally, the target RNA activates the collateral cleavage ability of CRISPR/Cas13a, and the reporter RNA is cleaved for third signal amplification. The detection limit of the proposed method is down to 1 cell mL-1. Furthermore, the tFNAs-Cas13a system is also shown to be capable of detecting rare tumor cells in spiked-in samples and clinical blood samples. This platform enables speedy detection of rare tumor cells with high sensitivity and good specificity, and shows great potential for tumor diagnosis.

A portable smartphone-based hemoglobin point-of-care testing platform for accurate anemia diagnostics.

Anemia affects over 2 billion people worldwide, with the heaviest burden borne by women and children. At present, anemia is diagnosed by measuring hemoglobin (Hb) levels, which must be done in hospitals or commercial laboratories by skilled operators. In this work, we report a portable, affordable ($3), easy-to-operate (1 min) and accurate smartphone-based Hb analyzer (SHbA) that uses a drop of finger-pricked blood for anemia point-of-care test (POCT) applications. POCT of Hb was achieved using a smartphone ambient light sensor (ALS) to accurately measure the absorbance of colorimetric Hb biochemical analysis reagents in a microcuvette, as well as an Android-based application for results analysis. SHbA validation results agreed well with those reported by a hematology analyzer, and the SHbA has an anemia diagnosis sensitivity of 95.4% and specificity of 96.3% for venous blood (n = 360) and a sensitivity of 96.39% and specificity of 95.58% for fingertip blood (n = 475). In addition, SHbA exhibits excellent performance in the diagnosis and treatment guidance of anemia high-risk populations, including tumor chemotherapy patients (n = 424), pregnant women (n = 214) and thalassemia patients (n = 208). Importantly, volunteer self-testing results (n = 20) indicate that SHbA can be used for home-based anemia diagnosis and monitoring. SHbA has the advantages of high sensitivity and specificity while being cheap and easy to operate, making it widely applicable for the diagnosis and treatment of anemia, especially for high-risk patients in areas with poor medical resources.

Point-of-Care Urinalysis with One Drop of Sample Using an Aggregation-Induced Emission Luminogen under the Coffee-Ring Effect.

Development of a practical point-of-care test for urinalysis is crucial for early diagnosis and treatment of chronic kidney disease (CKD). However, the classical gold standard detection method depends on sophisticated instruments and complicated procedures, impeding them from being utilized in resource-limited settings and daily screening. Herein, we report a rapid point-of-care device for the simultaneous quantification of microalbuminuria and leukocyte using one drop of urine. A luminogen (TTVP) with an aggregation-induced emission property can selectively activate its near-infrared fluorescence in the presence of albumin and leukocyte via hydrophobic or electrostatic interactions. The fluorescence signals from urine albumin and leukocyte could be well-separated combined with the coffee-ring effect. Using a smartphone-based detection device, simultaneous quantification of urine albumin and leukocyte was successfully achieved, which only took 20 min and required one drop of urine. The performance of this system is also verified with 120 clinical samples, which might serve as a simple, low-cost, and rapid tool for CKD screening and disease monitoring at the point of care.

Specific and Quantitative Detection of Albumin in Biological Fluids by Tetrazolate-Functionalized Water-Soluble AIEgens.

The analysis of albumin has clinical significance in diagnostic tests and obvious value to research studies on the albumin-mediated drug delivery and therapeutics. The present immunoassay, instrumental techniques, and colorimetric methods for albumin detection are either expensive, troublesome, or insensitive. Herein, a class of water-soluble tetrazolate-functionalized derivatives with aggregation-induced emission (AIE) characteristics is introduced as novel fluorescent probes for albumin detection. They can be selectively lighted up by site-specific binding with albumin. The resulting albumin fluorescent assay exhibits a low detection limit (0.21 nM), high robustness in aqueous buffer (pH = 6-9), and a broad tunable linear dynamic range (0.02-3000 mg/L) for quantification. The tetrazolate functionality endows the probes with a superior water solubility (>0.01 M) and a high binding affinity to albumin (KD = 0.25 µM). To explore the detection mechanism, three unique polar binding sites on albumin are computationally identified, where the multivalent tetrazolate-lysine interactions contribute to the tight binding and restriction of the molecular motion of the AIE probes. The key role of lysine residues is verified by the detection of poly-l-lysine. Moreover, we applied the fluorogenic method to quantify urinary albumin in clinical samples and found it a feasible and practical strategy for albumin analysis in complex biological fluids.