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CRISPR/Cas12a shows excellent potential in disease diagnostics. However, insensitive signal conversion strategies hindered its application in detecting protein biomarkers. Here, we report a metal-organic framework (MOF)-based DNA bio-barcode integrated with the CRISPR/Cas12a system for ultrasensitive detection of protein biomarkers. In this work, zirconium-based MOF nanoparticles were comodified with antibodies and bio-barcode phosphorylated DNA as an efficient signal converter, which not only recognized the protein biomarker to form the sandwich complex but also released the bio-barcode DNA activators after MOF dissociation to activate the trans-cleavage activity of Cas12a. Due to the obvious advantages, including numerous loaded oligonucleotides, a convenient release process, and the nontoxic release reagent, this MOF-DNA bio-barcode strategy could amplify the CRISPR/Cas12a system to achieve simple and highly sensitive detection of tumor protein biomarkers with detection limits of 0.03 pg/mL (PSA) and 0.1 pg/mL (CEA), respectively. Furthermore, this platform could detect PSA directly in clinical serum samples, offering a powerful tool for early disease diagnosis.

CRISPR/Cas12a has shown great potential in molecular diagnostics, but its application in sensing of microRNAs (miRNAs) was limited by sensitivity and complexity. Here, we have sensitively and conveniently detected microRNAs by reasonably integrating metal-organic frameworks (

Near-infrared (NIR)-light-triggered photothermal therapy (PTT) is usually associated with undesirable damage to healthy organs nearby due to the high temperatures (>50 °C) available for tumor ablation. Low-temperature PTT would therefore have tremendous value for clinical application. Here, we construct a hypoxia-responsive gold nanorods (AuNRs)-based nanocomposite of CRISPR-Cas9 for mild-photothermal therapy via tumor-targeted gene editing. AuNRs are modified with azobenzene-4,4'-dicarboxylic acid (p-AZO) to achieve on-demand release of CRISPR-Cas9 using hypoxia-responsive azo bonds. In the hypoxic tumor microenvironment, the azo groups of the hypoxia-activated CRISPR-Cas9 nanosystem based on gold nanorods (APACPs) are selectively reduced by the overexpression of reductases, leading to the release of Cas9 and subsequent gene editing. Owing to the knockout of HSP90α for reducing the thermal resistance of cancer cells, highly effective tumor ablation both in vitro and in vivo was achieved with APACPs under mild PTT.

Effective activation of cGAS-STING pathway combined with immune checkpoint blockade (ICB) within the immunosuppressive tumor microenvironment to induce stronger immune responsiveness yet remains challenging. CRISPR-Cas9 gene editing technology, which offers the benefits of permanence and irreversibility, could recognize the target genome sequence with sgRNA (Guide RNA) and guide the Cas9 protease to knock down the target gene. Herein, a nanoplatform (HMnMPH) for dual activation of cGAS-STING pathway in combination with CRISPR-Cas9 gene editing to silence programmed death ligand 1 (PD-L1) to trigger long-term immunotherapy was reported. The HMnMPH consists of hollow manganese dioxide (HMn) loaded with STING agonist (MSA-2) and CRISPR-Cas9/sg-PD-L1 plasmid with further modification of hyaluronic acid (HA). In acidic and GSH overexpressed tumor environment, HMnPMH was degraded to release large amounts of Mn ions and STING agonists, strongly and persistently activating the cGAS-STING pathway to promote the release of type I interferon and pro-inflammatory factors. Meanwhile, the released CRISPR-Cas9 plasmid could knockdown the PD-L1 immune checkpoint and restart immunosuppressive T cells to differentiate into cytotoxic T lymphocytes significantly, which reduced the activity of primary and distal tumors and demonstrated a long-term immune memory effect on distal tumors.

Light has been present throughout the history of mankind and even the universe. It is of great significance to human life, contributing to energy, agriculture, communication, and much more. In the biomedical field, light has been developed as a switch to control medical processes with minimal invasion and high spatiotemporal selectivity. During the past three years, near-infrared (NIR) light as long-wavelength light has been applied to more than 3000 achievements in biological applications due to its deep penetration depth and low phototoxicity. Remotely controlled cancer therapy usually involves the conversion of biologically inert NIR light. Thus, various materials, especially nanomaterials that can generate reactive oxygen species (ROS), ultraviolet (UV)/visual light, or thermal energy and so on under NIR illumination achieve great potential for the research of nanomedicine. Here, we offered an overview of recent advances in NIR light-activated nanomedicine for cancer therapeutic applications. NIR-light-conversion nanotechnologies for both directly triggering nanodrugs and smart drug delivery toward tumor therapy were discussed emphatically. The challenges and future trends of the use of NIR light in biomedical applications were also provided as a conclusion. We expect that this review will spark inspiration for biologists, materials scientists, pharmacologists, and chemists to fight against diseases and boost the future clinical-translational applications of NIR technology-based precision nanomedicine.

We report gold nanoparticles (AuNPs) doped iron-based metal-organic frameworks (GIM) which displays near-infrared light (NIR)-enhanced cascade nanozyme against hypoxic tumors. Due to the strong protein adsorption-induced surface passivation, AuNPs suffer from the loss of glucose oxidase (GOx) activity. However, GIM could protect the GOx-like activity of AuNPs with the satisfactory shield capability. In addition, GIM exhibited excellent photothermal conversion ability and unique NIR light-enhanced GOx-like activity, which could efficiently increase the endogenous H2O2 production. Meanwhile, as the produced H2O2 is converted by GIM into O2 and highly toxic OH. Thus, GIM-catalyzed cascade reactions with NIR light irradiation not only offer the O2 but also promote the reactive oxygen species (ROS) generation at tumor sites. The produced O2 could be further applied to AuNPs catalytic oxidation of glucose and relieve hypoxic condition of tumor microenvironment (TME). As a proof-of-concept study, GIM demonstrates the admirable tumor ablation under NIR irradiation in vivo.

The previous clinical trials found that the co-administration of irinotecan with sunitinib exhibited a synergistic antitumor effect. In the current study, we aimed to investigate whether the synergistic effect is related to a potential pharmacokinetic interaction between sunitinib and irinotecan. The inhibitory effects of sunitinib on SN-38 glucuronidation were determined by measuring the formation rates for SN38 glucuronide using recombinant human UGT isoforms and human liver microsomes (HLMs) in the absence or presence of sunitinib. Our data indicated that sunitinib exhibited competitive inhibition against SN-38 glucuronidation by UGT1A1, but inhibitory effects of sunitinib were weak in pooled human liver microsomes (HLMs) (Ki = 119.00 μM) and recombinant UGT1A1 (Ki = 42.71 μM). Our further prediction study partly explains the possible mechanism of synergistic antitumor activity of sunitinib and irinotecan in the combined treatment and provides a basis for design of clinical studies for the development and optimization of this combination.

Cancer has become a leading cause of morbidity and mortality, and there is an increasing need for versatile tools to enable sensitive, simple and early cancer monitoring. Here, we report platinum supernanoparticles as an exogenous nanosensor which can dissociate into ultrasmall platinum nanoclusters (PtNCs) under tumor-specific hypoxia conditions. The resulting PtNCs can be filtered through the kidney as urinary reporters to be quantified by a companion volumetric bar-chart chip (V-Chip) for point-of-care analysis. The V-Chip signals of triple-negative breast cancer and its lung metastasis mouse model showed a significant increase compared to healthy mice. Our nanosensor can also noninvasively monitor the course of treatment, which is significant for screening tumor recurrence and individualized evaluation of pharmacological and follow-up efficacy. Importantly, this strategy could be adapted for various diseases to form a common diagnostic platform by changing responsive linkers.

In addition to applications in genome editing, clustered regularly interspaced short palindromic repeats (CRISPR) have recently been engineered for medical diagnostics based on their trans-cleavage activity owing to their high base resolution and isothermal signal amplification. However, trans-cleavage activity is too fragile to be applied in vivo. Herein, we introduce a hollow covalent organic framework (COF)-sheltering CRISPR/aptamer-based sensor (h-CCS) for ATP imaging in living animals. The CRISPR/aptamer-based complex is comprised of the CRISPR-Cas12a system, fluorophore quencher-labeled single-stranded DNA substrate (ssDNA-FQ), and a DNA activator that pre-hybridizes with ATP aptamer to prevent the trans-cleavage activity of the Cas12a system in the absence of ATP. After being encapsulated in a hollow COF, the constructed nanoreactor is highly robust and can be lit up by ATP for in vivo imaging. Considering the unique properties of h-CCS, this strategy offers great potential to broaden applications of not only CRISPR-Cas systems but also other proteins in porous matrixes for clinical diagnostics, medical research, and biomimetic nanodevices.

Cytochrome P450 2C9 (CYP2C9) is capable of catalyzing the biotransformation of endogenous compounds in cells, indicating that this enzyme could change the intracellular environment and is related to the pathogenesis of diseases. Currently, it is still a challenge to study the differences in cellular components between CYP2C9-expressing and non-expressing cells. In this study, employing a Au nanoparticles–Ag nanowires (AuNPs–AgNWs) decorated silicon wafer as a novel non-destructive and label-free tool, we applied surface-enhanced Raman scattering (SERS) spectroscopy to detect and distinguish the cellular composition of CYP2C9-expressing cells (293T-Mig-2C9) and non-expressing cells (293T-Mig-R1). AgNWs with high surface roughness were formed by modification of AuNPs onto their surface by electrostatic interactions, which enabled them to exhibit greatly enhanced SERS ability. Then, they were employed to fabricate SERS substrates via an electrostatically assisted 3-aminopropyltriethoxysilane (APTES)-functionalized surface-assembly method. The SERS substrates exhibited high sensitivity with a detection limit of 1 × 10−9 M for 4-mercaptobenzoic acid (4-MBA). Meanwhile, the SERS substrates exhibited good uniformity and reproducibility. The cytotoxicity assay demonstrated that the SERS substrates displayed good biocompatibility with 293T cells. Before SERS measurements, CYP2C9 constantly expressed cells (293T-Mig-2C9 cells) and control cells (293T-Mig-R1 cells) were constructed. The expression of CYP2C9 and the catalytic activity in the cells were checked. Using the AuNPs–AgNWs substrates as a high-performance in vitro sensing platform allowed us to obtain fingerprint spectra of 293T-Mig-R1 and 293T-Mig-2C9 cells. The difference spectra between the two cell lines were studied to interpret the spectral differences and gain insight into the biochemical variations. Finally, principal component analysis (PCA) score plots of the SERS spectra were also used to better view the differences between the two cell lines. SERS detection based on the AuNPs–AgNWs substrates provides a sensitive, non-destructive and label-free method for differentiation between 293T-Mig-R1 and 293T-Mig-2C9 cells.

Inflammatory bowel disease (IBD) is a chronic relapsing autoimmune disease that is characterized by segmental intestinal inflammation. There is an urgent need for more efficient inflammation-targeting strategies to improve therapeutic effect and reduce systemic drug exposure. Herein, an oxidation-responsive metal-organic framework material (Ce-MOF@PSS) is reported that preferentially adheres to inflamed intestine via enema. The overproduced reactive oxygen species (ROS) at inflammatory sites induces transformation of Ce-MOF@PSS from mesopore to macropore with local drug release. In experimental colitis, the Ce-MOF@PSS delivery system exhibits excellent inflammation-targeting efficacy and superior therapeutic effect over free drug on suppressing inflammation and repairing intestinal barrier function. Accordingly, by targeting intestinal inflammation, increasing local drug concentrations, scavenging ROS, reducing systemic exposure, and exhibiting excellent safety profiles, it is considered that the Ce-MOF drug delivery platform can be intensively developed as a translational nanomedicine for the management of IBD and other inflammatory diseases.

In this study, we constructed a glutathione (GSH)-triggered MSNs@MOF nanoreactor, in which Cu (II) was coordinated with trimesic acid (BTC) to form a shell. Cu (I) produced via in situ reduction with GSH acted as a catalyst, which further expedited the rate of the bioorthogonal reaction between alkyne and azide. We assessed the performance of our nanoreactors for GSH sensing, ranging from cells to wheat plumules. The results show that our nanoreactors possess good biocompatibility and have potential applications in the detection of metal ions in plants. The ability to monitor bioorthogonal reactions intracellularly may contribute to precision chemistry for rational designs of smart platforms for biomarker detection beyond GSH and targeted drug manufacture for precision medicine.

Remote-controlled manipulation of gene editing was achieved in vivo., As an RNA-guided nuclease, CRISPR-Cas9 offers facile and promising solutions to mediate genome modification with respect to versatility and high precision. However, spatiotemporal manipulation of CRISPR-Cas9 delivery remains a daunting challenge for robust effectuation of gene editing both in vitro and in vivo. Here, we designed a near-infrared (NIR) light–responsive nanocarrier of CRISPR-Cas9 for cancer therapeutics based on upconversion nanoparticles (UCNPs). The UCNPs served as “nanotransducers” that can convert NIR light (980 nm) into local ultraviolet light for the cleavage of photosensitive molecules, thereby resulting in on-demand release of CRISPR-Cas9. In addition, by preparing a single guide RNA targeting a tumor gene (polo-like kinase-1), our strategies have successfully inhibited the proliferation of tumor cell via NIR light–activated gene editing both in vitro and in vivo. Overall, this exogenously controlled method presents enormous potential for targeted gene editing in deep tissues and treatment of a myriad of diseases.

This work prepared a Cerium metal organic framework (Ce-MOF), which exhibits colorimetric and fluorescent response for H2O2 simultaneously. The Ce-MOF was integrated in the origami paper SlipChip to directly analyze glucose and uric acid level in serum without sample handling or extra analytical equipment except for a smartphone. Its excellent stability in wide pH and temperature, which ranges from pH 1 to 12 and from 20 to 90 °C respectively, provides wider application prospects than conventional colorimetric strategy in the horseradish peroxidase (HRP) based detection. In colorimetric assays, the "coffee ring effect" is a fatal problem which refers to the instable and inhomogeneous color rendering, and the coating of color rendering zones by dried serum proteins also seriously hinders color reading. Herein, the anchored Ce-MOF not only solves the "coffee ring effect" by modulating the mass transport, but also constructs an ingenious bio-like barrier for selectively blocking proteins in serum. To achieve that, the externally actuated strategy and Ce-MOF mediating molecular threading-dependent transport strategy were employed. Relatively good performance of our device has been demonstrated whatever in color stability and uniformity, serum protein filtration or the direct clinical sample diagnosis.