Accelerated and precise identification of antioxidants and pesticides using a smartphone-based colorimetric sensor array.

The integration of smartphones with conventional analytical approaches plays a crucial role in enhancing on-site detection platforms for point-of-care testing. Here, we developed a simple, rapid, and efficient three-channel colorimetric sensor array, leveraging the peroxidase (POD)-like activity of polydopamine-decorated FeNi foam (PDFeNi foam), to identify antioxidants using both microplate readers and smartphones for signal readouts. The exceptional catalytic capacity of PDFeNi foam enabled the quick catalytic oxidation of three typical peroxidase substrates (TMB, OPD and 4-AT) within 3 min. Consequently, we constructed a colorimetric sensor array with cross-reactive responses, which was successfully applied to differentiate five antioxidants (i.e., glycine (GLY), glutathione (GSH), citric acid (CA), ascorbic acid (AA), and tannic acid (TAN)) within the concentration range of 0.1-10 µM, quantitatively analyze individual antioxidants (with AA and CA as model analytes), and assess binary mixtures of AA and GSH. The practical application was further validated by discriminating antioxidants in serum samples with a smartphone for signal readout. In addition, since pesticides could be absorbed on the surface of PDFeNi foam through π-π stacking and hydrogen bonding, the active sites were differentially masked, leading to featured modulation on POD-like activity of PDFeNi foam, thereby forming the basis for pesticides discrimination on the sensor array. The nanozyme-based sensor array provides a simple, rapid, visual and high-throughput strategy for precise identification of various analytes with a versatile platform, highlighting its potential application in point-care-of diagnostic, food safety and environmental surveillance.

Unexpected Emergence of Carbon-Centered Radicals from Piezoelectric Effect in Oleic Acid-Capped BaTiO3.

The utilization of alkyl radicals (•R) for hypoxic tumor therapy has great prospects due to its O2-independence and high reactivity. However, correlational initiators for in vivo activation remain scarce. Here, we report that ultrasound excitation of oleic acid-capped BaTiO3 (OA@BaTiO3) can result in an •R cascade and hence a means to conquer hypoxic tumors. Mechanistic studies find that the •R signal disappears when OA@BaTiO3 undergoes acid washing post-treatment, which is a common procedure for removing the unwanted byproduct BaCO3. Combined with the infrared spectrum analysis, acid treatment was proven to weaken the peaks at 2840-2970 cm-1 characteristic of -CH2- and terminal -CH3 stretching vibration of OA. There is compelling evidence that high temperature thermal oxidation of OA involves the generation of •R. Thus, acid washing is considered to remove the loosely bound yet catalytically active OA. And piezoelectric BaTiO3, a potential electron-hole redox catalyst, can sensitize these OA molecules and disintegrate them to •R. This unexpected discovery provides us with a distinctive mentality to seek diverse •R initiators for tumor ablation, as well as an additional perspective on the postprocessing of synthetic materials.

Self-Assembly of 2D Polyphthalocyanine in Lysosome Enables Multienzyme Activity Enhancement to Induce Tumor Ferroptosis.

Nanozymes show great potential in facilitating tumor ferroptosis by upregulation of reactive oxygen species (ROS) and downregulation of glutathione (GSH). However, mild acidity (pH 6.5-6.9) of tumor microenvironment severely restricts the activity of nanozymes. Although lysosomes as acidic organelles (pH = 3.5-5.5) are hopeful for improving enzyme-like activity, most reported nanozymes are not capable of effectively accumulating in the lysosomes. Herein, an acid-responsive self-assembly strategy based on iron phthalocyanine-rich covalent organic framework nanosheets (COFFePc NSs) is developed, which enables lysosomal targeting aggregation of COFFePc NSs due to the existence of abundant negative hydroxyl groups and rigid structure. Meanwhile, COFFePc NSs display exceptional multienzyme-mimic performance at lower pH to efficiently generate ROS to cause lysosome damage and apoptosis by synergistic photothermal effect. Subsequently, the released COFFePc with GSH oxidase-mimicking activity can consume GSH to promote ferroptosis. This is the first report of a 2D COF using its own properties to achieve lysosomal self-assembly. Overall, the work provides a new paradigm for the development of lysosome-targeted nanosystems.

A cascade nanoplatform for intelligent response to tumor microenvironment and collaborative cancer therapy.

Disulfiram (DSF), a new potential anticancer drug, has been shown to exhibit anticancer activity dependent on the formation of CuET, the chelation product of DSF with Cu2+. However, the poor stability of DSF and insufficient physiological concentration of Cu2+ hinder its practical application. To achieve the co-delivery of DSF and Cu2+ while overcoming the inefficiency of single chemotherapy, in this study, a cascade nanoplatform, DSF/Ce6@ZIF-8@CuO2, was constructed by encapsulating DSF and chlorin e6 (Ce6, a photosensitizer) in zeolite imidazole framework-8 (ZIF-8, a nanocarrier) and then loading CuO2, which self-supplied H2O2/O2, onto DSF/Ce6@ZIF-8. By triggering the response of DSF/Ce6@ZIF-8@CuO2 to the acidic tumor microenvironment, encapsulated DSF, Ce6 and CuO2 were released to achieve multimodal synergistic treatment with enhanced DSF chemotherapy and chemodynamic/photodynamic therapy (CDT/PDT). In vitro and animal studies indicated that the designed DSF/Ce6@ZIF-8@CuO2 has strong tumor-inhibitory effects and provides a promising paradigm for designing smart nanoplatforms.

Near-Infrared Light-Enhanced Generation of Hydroxyl Radical for Cancer Immunotherapy.

Hydroxyl radical (• OH) as a highly oxidizing reactive oxygen species can induce immunogenic cell death (ICD) in cancer treatment. However, high-efficiency cancer immunotherapy is still a huge challenge due to the low • OH generation efficiency in the tumor microenvironment, resulting in insufficient immunogenicity and the poor immune response. Here, a near-infrared (NIR) light-enhanced • OH generation strategy is developed for cancer immunotherapy by using a copper-based metal-organic framework (Cu-DBC) nanoplatform. With this strategy, the generation efficiency of • OH under NIR irradiation is increased 7.34 times than that without NIR irradiation, which induces robust ICD and immune response, thus leading to primary tumor elimination and the inhibition of distant tumor growth and tumor lung metastasis. Experimental results show that Cu-DBC can induce • OH boosting through photothermal (PT)-enhanced Cu-catalytic Fenton-like reaction and photocatalytic electron transfer under NIR light irradiation to amplify tumor ICD for immunotherapy.

Rational Utilization of Black Phosphorus Nanosheets to Enhance Palladium-Mediated Bioorthogonal Catalytic Activity for Activation of Therapeutics.

Pd-catalyzed chemistry has played a significant role in the growing subfield of bioorthogonal catalysis. However, rationally designing Pd nanocatalysts that show outstanding catalytic activity and good biocompatibility poses a great challenge. Herein, we propose an innovative strategy through exploiting black phosphorous nanosheets (BPNSs) to enhance Pd-mediated bioorthogonal catalytic activity. Firstly, the electron-donor properties of BPNSs enable in situ growth of Pd nanoparticles (PdNPs) on it. Meanwhile, due to the superb capability of reducing PdII , BPNSs can act as hard nucleophiles to accelerate the transmetallation in the decaging reaction process. Secondly, the lone pair electrons of BPNSs can firmly anchor PdNPs on their surface via Pd-P bonds. This design endows Pd/BP with the capability to retard tumor growth by activating prodrugs. This work proposes new insights into the design of heterogeneous transition-metal catalysts (TMCs) for bioorthogonal catalysis.

Calcination-controlled performance optimization of iron-vanadium bimetallic oxide nanoparticles for synergistic tumor therapy.

Calcination has been widely demonstrated as a favorable protocol for producing various inorganic nanomaterials for tumor therapy. However, little attention has been paid to its effect on the biotherapeutic efficacy of inorganic nanomaterials. Herein, we compare the effects of different calcination atmospheres on the therapeutic efficacy of Fe-V-O (FVO) nanomaterials. We find that compared with FVO nanomaterials synthesized by calcination in air, those prepared by argon calcination have a lower metallic valence state and a higher near-infrared light absorption capacity, hence resulting in significantly better biosafety and higher chemodynamic therapy (CDT)/photothermal therapy (PTT) efficacy. This study demonstrates that the therapeutic efficacy of inorganic nanomaterials can be optimized by employing different thermal treatment atmospheres, which provides new insights into the development of efficient anti-tumor agents.

Engineering a synergistic antioxidant inhibition nanoplatform to enhance oxidative damage in tumor treatment.

The antioxidant system of tumor cells severely impairs reactive oxygen species (ROS)-mediated tumor therapy. Despite extensive attempts to attenuate the antioxidant capacity by eliminating ROS scavengers such as glutathione (GSH), nicotinamide adenine dinucleotide phosphate (NADPH) over-expressed in the tumor microenvironment can regenerate GSH from glutathione disulfide (GSSG), hence weakening ROS-induced oxidative damage. Therefore, engineering a nanoplatform capable of depleting both NADPH and GSH is extremely significant for improving ROS-mediated tumor treatment. Herein, a synergetic antioxidant inhibition strategy is proposed to attenuate intracellular antioxidant capacity for hypoxic tumor therapy. In this context, both porous Prussian blue nanoparticles (PPB NPs) and cisplatin prodrug [cis-Pt (IV)] in the nanoplatform can oxidize GSH to directly reduce GSH levels, while PPB NPs also enable NADPH depletion by peroxidase-mimicking to impair GSH regeneration. Furthermore, PPB NPs with catalase-mimicking activity catalyze H2O2 decomposition to alleviate tumor hypoxia, thus reducing the generation of GSH and boosting singlet oxygen (1O2) production by Chlorin e6 (Ce6) for enhancing oxidative damage. Experimental results prove that the nanoplatform, denoted as PPB-Ce6-Pt, can induce remarkable tumor cells apoptosis and ferroptosis. Importantly, a simple loading method and the use of Food Drug Administration (FDA)-approved materials make PPB-Ce6-Pt have great potential for practical applications. STATEMENT OF SIGNIFICANCE: The antioxidant system in tumor cells disables ROS-mediated tumor therapy. Besides, extensive attempts aim at depleting GSH without considering their regeneration. Therefore, we developed a synergetic strategy to attenuate intracellular antioxidant capacity for hypoxic tumor therapy. PPB-Ce6-Pt nanoplatform could not only directly reduce GSH levels but also deplete NADPH by peroxidase-mimicking to impair GSH regeneration. In addition, PPB-Ce6-Pt nanoplatform could catalyze H2O2 decomposition to alleviate tumor hypoxia, thus reducing the generation of GSH and boosting 1O2 production by Chlorin e6 (Ce6) for increasing oxidative damage. Then, intracellular ROS boost and redox dyshomeostasis induced remarkable tumor cells apoptosis and ferroptosis. Importantly, a simple loading method and the use of biosafety materials made the nanoplatform have great potential for practical applications.

A mitochondria targeted cascade reaction nanosystem for improved therapeutic effect by overcoming cellular resistance.

Mitigating cellular resistance, which could enhance the sensitivity of tumor cells to treatment, is a promising approach for obtaining better therapeutic outcomes. However, the present designs of materials generally disregard this point, or only focus on a single specific resistance. Herein, a strategy based on a series of cascade reactions aiming to suppress multiple cellular resistances is designed by integrating photothermal and chemotherapy into a mitochondria targeted nanosystem (AuBPs@TD). The intelligent nanosystem is fabricated by modifying gold nanobipyramids (AuBPs) with triphenylphosphonium (TPP) functionalized dichloroacetic acid (DCA). TPP serves as a "navigation system" and facilitates the location of AuBPs@TD in the mitochondria. Moreover, the released DCA promoted by the photothermal effect of AuBPs, as the mitochondrial kinase inhibitor, could inhibit glycolysis, and lead to a repressed expression of heat shock protein 90, which is the main resistance protein in cancer cells against photothermal therapy (PTT). Thus, the photothermal antitumor effect can be significantly improved. For the other cascade passage, the hyperthermal atmosphere depresses the expression of P-glycoprotein, a protein associated with drug resistance, and consequently prevents DCA molecules from being expelled in return. Furthermore, the retained DCA molecules elevate the concentration of intracellular hydrogen peroxide, and due to the peroxidase-like activity of AuBPs, increased intracellular reactive oxygen species could be obtained to accelerate apoptosis. As a result, these cascade reactions lead to significant inhibition of cellular resistance and greatly improve the therapeutic performance. This work paves a new way for suppressing cellular resistance to achieve the desired therapeutic effect.

Dual-responsive nano-prodrug micelles for MRI-guided tumor PDT and immune synergistic therapy.

Micelles as nanocarriers not only offer new opportunities for early diagnosis and treatment of malignant cancers but also encounter numerous barriers in the path of efficient delivery of drugs to diseased areas in the body. To address these issues, we developed a pH/GSH responsive nano-prodrug micelle (NLG919/PGA-Cys-PPA@Gd) with a high drug-loading ratio and controlled drug release performance for MRI-guided tumor photodynamic therapy (PDT) and immune synergistic therapy. Under normal conditions, theranostic nanomicelles remained stable and in a photo-quenched state. Upon accumulation in the tumor site, however, the micelles demonstrated tumor microenvironment (TME) triggered photoactive formed-PPA (a photosensitizer) and NLG919 (an indoleamine 2,3-dioxygenase (IDO) inhibitor) release because the amide bonds of PGA-Cys-PPA and the disulfide linkage of Cys were sensitive to pH and GSH, respectively. More importantly, these micelles could avoid the undesired PPA leakage in blood circulation due to the conjugation between PPA and polymers. Furthermore, the obtained micelles could also enhance the contrast of T1-weighted MRI of tumors by virtue of their high relaxivity (r1 = 29.85 mM-1 s-1). In vitro and in vivo results illustrated that the micelles had good biocompatibility and biosafety. On the basis of the efficient drug delivery strategies in PDT and IDO pathway inhibition, this intelligent dual-drug delivery system could serve as an effective approach for MRI guided combination therapy of cancer.

Mitochondria-Targeting Enhanced Phototherapy by Intrinsic Characteristics Engineered "One-for-All" Nanoparticles.

Mitochondria-targeted synergistic therapy, including photothermal (PTT) and photodynamic therapy (PDT), has aroused wide attention due to the high sensitivity to reactive oxygen species (ROS) and heat shock of mitochondria. However, most of the developed nanosystems for the combinatorial functions require the integration of different components, such as photosensitizers and mitochondria-targeted molecules. Consequently, it indispensably requires sophisticated design and complex synthetic procedures. In this work, a well-designed Bi2S3-based nanoneedle, that localizes to mitochondria and produces extra ROS with inherent photothermal effect, was reported by doping of Fe (denoted as FeBS). The engineered intrinsic characteristics certify the capacity of such "one-for-all" nanosystems without additional molecules. The lipophilicity and surface positive charge are demonstrated as crucial factors for specifical mitochondria targeting. Significantly, Fe doping overcomes the disadvantage of the narrow band gap of Bi2S3 to prevent the fast recombination of electron-hole, hence resulting in the generation of ROS for PDT. The "one-for-all" nanoparticles integrate with mitochondria-targeting and synergistic effect of PDT and PTT, thus exhibit enhanced therapeutic effect and inhibit the growth of tumors observably. This strategy may open a new direction in designing the mitochondria-targeted materials and broadening the properties of inorganic semiconductor materials for satisfactory therapeutic outcomes.

Defect Engineering Enables Synergistic Action of Enzyme-Mimicking Active Centers for High-Efficiency Tumor Therapy.

Perusing redox nanozymes capable of disrupting cellular homeostasis offers new opportunities to develop cancer-specific therapy, but remains challenging, because most artificial enzymes lack enzyme-like scale and configuration. Herein, for the first time, we leverage a defect engineering strategy to develop a simple yet efficient redox nanozyme by constructing enzyme-mimicking active centers and investigated its formation and catalysis mechanism thoroughly. Specifically, the partial Fe doping in MoOx (donated as Fe-MoOv) was demonstrated to activate structure reconstruction with abundant defect site generation, including Fe substitution and oxygen vacancy (OV) defects, which significantly enable the binding capacity and catalytic activity of Fe-MoOv nanozymes in a synergetic fashion. More intriguingly, plenty of delocalized electrons appear due to Fe-facilitated band structure reconstruction, directly contributing to the remarkable surface plasmon resonance effect in the near-infrared (NIR) region. Under NIR-II laser irradiation, the designed Fe-MoOv nanozymes are able to induce substantial disruption of redox and metabolism homeostasis in the tumor region via enzyme-mimicking cascade reactions, thus significantly augmenting therapeutic effects. This study that takes advantage of defect engineering offers new insights into developing high-efficiency redox nanozymes.

An All-in-One Organic Semiconductor for Targeted Photoxidation Catalysis in Hypoxic Tumor.

Tumor hypoxia severely limits the therapeutic effects of photodynamic therapy (PDT). Although many methods for oxygen generation exist, substantial safety concerns, spatiotenporal uncontrollability, limited efficacy, and complicated procedures have compromised their practical application. Here, we demonstrate a biocompatiable all-in-one organic semiconductor to provide a photoxidation catalysis mechanism of action. A facile method is developed to produce gram-level C5 N2 nanoparticles (NPs)-based organic semiconductor. Under 650 nm laser irradiation, the semiconductor split water to generate O2 and simultaneously produce singlet oxygen (1 O2 ), showing that the photocatalyst for O2 evolution and the photosensitizer (PS) for 1 O2 generation could be synchronously achieved in one organic semiconductor. The inherent nucleus targeting capacity endows it with direct and efficient DNA photocleavage. These findings pave the way for developing organic semiconductor-based cancer therapeutic agents.

On-demand degradable magnetic resonance imaging nanoprobes.

Theranostic nanoprobes can potentially integrate imaging and therapeutic capabilities into a single platform, offering a new personalized cancer diagnostic tool. However, there is a growing concern that their clinical application is not safe, particularly due to metal-containing elements, such as the gadolinium used in magnetic resonance imaging (MRI). We demonstrate for the first time that the photothermal melting of the DNA duplex helix was a reliable and versatile strategy that enables the on-demand degradation of the gadolinium-containing MRI reporter gene from polydopamine (PDA)-based theranostic nanoprobes. The combination of chemotherapy (doxorubicin) and photothermal therapy, which leads to the enhanced anti-tumor effect. In vivo MRI tracking reveals that renal filtration was able to rapidly clear the free gadolinium-containing MRI reporter from the mice body. This results in a decrease in the long-term toxic effect of theranostic MRI nanoprobes. Our findings may pave the way to address toxicity issues of the theranostic nanoprobes.

Targeted Engineering of Medicinal Chemistry for Cancer Therapy: Recent Advances and Perspectives.

Severe side effects and poor therapeutic efficacy are the main drawbacks of current anticancer drugs. These problems can be mitigated by targeting, but the targeting efficacy of current drugs is poor and urgently needs improvement. Taking this into consideration, this Review first summarizes the current targeting strategies for cancer therapy in terms of cancer tissue and organelles. Then, we analyse the systematic targeting of anticancer drugs and conclude that a typical journey for a targeted drug administered by intravenous injection is a CTIO cascade of at least four steps. Furthermore, to ensure high overall targeting efficacy, the properties of a targeting drug needed in each step are further analysed, and some guidelines for structure optimization to obtain effective targeting drugs are offered. Finally, some viewpoints highlighting the crucial problems and potential challenges of future research on targeted cancer therapy are presented. This review could actively promote the development of precision medicine against cancer.

Polypyrrole-based double rare earth hybrid nanoparticles for multimodal imaging and photothermal therapy.

Nanotheranostic agents that can simultaneously provide real-time tracking and accurate treatment at tumor sites are playing an increasingly important role in medicine. Herein, a novel polypyrrole (PPy)-based theranostic agent containing double rare-earth elements (PPy@BSA-Gd/Dy NPs) was successfully synthesized via an integrated strategy combining biomineralization and oxidation polymerization. The obtained PPy@BSA-Gd/Dy NPs with a diameter of approximately 59.48 ± 6.12 nm exhibited excellent solubility, long-term stability, superior biocompatibility, and negligible toxicity. Importantly, due to its intrinsic paramagnetic and strong X-ray attenuation ability, this agent demonstrated brilliant imaging performance in both T1/T2-weighted magnetic resonance imaging (MRI) and X-ray computed tomography (CT) imaging in vitro and vivo. Additionally, with an excellent photothermal conversion efficiency (26.61%) upon irradiation by an 808 nm laser, this theranostic agent showed significant photothermal cytotoxicity against HeLa cells and 4T1 cells in vitro and antitumor efficacy through intravenous injection in vivo. Meanwhile, biodistribution and blood circulation were also used to explore its fate in vivo. In summary, this study highlighted the versatility and practicability of PPy@BSA-Gd/Dy NPs and also suggested that the agent may be a promising candidate for T1/T2-weighted MRI/CT tri-modal imaging guided photothermal cancer therapy.

Nanoscaled porphyrinic metal-organic framework for photodynamic/photothermal therapy of tumor.

Nanoagents achieving photodynamic therapy (PDT) and photothermal therapy (PTT) combination treatment with improved therapeutic effect are highly desirable. However, the incorporation of both PDT and PTT into a single nanoagent often requires multistep fabrication process. Herein, we report that photoactive porphyrin ligands have been successfully introduced into Zn-TCPP structure to construct the nanoagents that possesses photodynamic performance and photothermal performance simultaneously. Such a nanoagent enables the generation of single oxygen and heat under laser irradiation. Additionally, it exhibits satisfactory biocompatibility and high light toxicity against cancer cells. The current work provides a feasible approach to introduce both PDT and PTT into a single nanoplatform.

A C5 N2 Nanoparticle Based Direct Nucleus Delivery Platform for Synergistic Cancer Therapy.

Intracellular targeting has the same potential as tissue targeting to increase therapy efficacy, especially for drugs that are toxic to DNA. By adjusting intracellular traffic, we developed a novel direct-nucleus-delivery platform based on C5 N2 nanoparticles (NPs). Supramolecular interactions of C5 N2 NPs with the cell membrane enhanced cell uptake; abundant edge amino groups promoted fast and effective rupture of early endosomes; and the appropriate size of the NPs was also crucial for size-dependent nuclear entry. As a proof of concept, the platform was not only suitable for the effective delivery of molecular drugs/dyes (doxorubicin, hydroxycamptothecine, and propidium iodide) and MnO2 nanoparticles to the nucleus, but was also photoresponsive for nucleus-targeting photothermal therapy (PTT) and photodynamic therapy (PDT) to further greatly increase anticancer efficacy. This strategy might open the door to a new generation of nuclear-targeted enhanced anticancer therapy.

Delineating the tumor margin with intraoperative surface-enhanced Raman spectroscopy.

The failure of complete tumor resection during cancer surgery is a leading cause of lethal recurrence and metastasis. However, achieving accurate delineation of tumor margins intraoperatively remains extremely difficult because the infiltrated nature of a tumor usually gives an obscure margin and spreading microtumors. Recent studies show that surface-enhanced Raman scattering (SERS) has the potential to depict precisely the actual tumor extent with high sensitivity, specificity, and spatial resolution; thus providing a promising platform to improve the therapeutic efficiency. In this review, we discuss the recent progress in the use of SERS spectroscopy for intraoperative image-guided resection. We highlight key successes in the development of SERS tags and give insights into the design mechanism of rational SERS tags. We also discuss how to improve the performance of intraoperative navigation based on SERS and explore the challenges and future opportunities for the development of a more effective SERS-based platform. Graphical abstract ᅟ.

CO2-based amphiphilic polycarbonate micelles enable a reliable and efficient platform for tumor imaging.

Biodegradable polymeric nanomaterials can be directly broken down by intracellular processes, offering a desirable way to solve toxicity issues for cancer diagnosis and treatment. Among them, aliphatic polycarbonates are approved for application in biological fields by the United States Food and Drug Administration (FDA), however, high hydrophobicity, deficient functionality and improper degradation offer significant room for improvement in these materials. METHODS: To achieve progress in this direction, herein, we demonstrate that CO2-based amphiphilic polycarbonates (APC) with improved hydrophilicity and processability can be used as a reliable and efficient platform for tumor imaging. To better investigate their potential, we devised a convenient strategy through conjugation of APC with gadolinium (Gd). RESULTS: The resulting polymeric micelles (APC-DTPA/Gd) exhibit excellent magnetic resonance imaging performance, simultaneously enabling real-time visualization of bioaccumulation and decomposition of polymeric micelles in vivo. Importantly, these micelles can be degraded to renally cleared products within a reasonable timescale without evidence of toxicity. CONCLUSION: Our findings may help the development of CO2-based amphiphilic polycarbonate for cancer diagnosis and treatment, accompanied by their low-toxicity degradation pathway.