Intracerebral Fluorescence-Photoacoustic Dual-Mode Imaging for Precise Diagnosis and Drug Intervention Tracing in Depression.

Unravelling the pathophysiology of depression is a unique challenge. Depression is closely associated with reduced norepinephrine (NE) levels; therefore, developing bioimaging probes to visualize NE levels in the brain is a key to elucidating the pathophysiological process of depression. However, because NE is similar in structure and chemical properties to two other catecholamine neurotransmitters, epinephrine and dopamine, designing an NE-specific multimodal bioimaging probe is a difficult task. In this work, we designed and synthesized the first near-infrared fluorescent-photoacoustic (PA) dual-modality imaging probe for NE (FPNE). The ß-hydroxyethylamine of NE was shown to react via nucleophilic substitution and intramolecular nucleophilic cyclization, resulting in the cleavage of a carbonic ester bond in the probe molecule and release of a merocyanine molecule (IR-720). This process changed the color of the reaction solution from blue-purple to green, and the absorption peak was red-shifted from 585 to 720 nm. Under light excitation at 720 nm, linear relationships between the concentration of NE and both the PA response and the fluorescence signal intensity were observed. Thus, the use of intracerebral in situ visualization for diagnosis of depression and monitoring of drug interventions was achieved in a mouse model by fluorescence and PA imaging of brain regions after administration of FPNE by tail-vein injection.

Mechanism underlying the effect of MnO2 nanosheets for A549 cell chemodynamic therapy.

MnO2 nanosheets (MnO2NSs) were synthesized by one-step method, and MnO2NSs were applied to A549 cell chemodynamic Therapy (CDT). The cytotoxicity, redox ability, and reactive oxygen species production of MnO2NSs have been investigated, and differences in cell metabolism during CDT were determined using liquid chromatography-mass spectrometry (LC-MS/MS). In addition, the metabolites of A549 lung cancer cells affected by MnO2NSs treatment are identified; metabolite differences were identified by PCA, PLS-DA, orthogonal PLS-DA, and other methods; and these differences were analyzed using non-targeted metabolomics. We found that A549 cells which were treated by MnO2NSs have 17 different metabolites and 9 metabolic pathways that varied markedly. Owing to their unique composition, structure, and physicochemical properties, MnO2NSs and their composites have become a favored type of nanomaterial used for CDT in cancer therapy. This work provides insights into the mechanism underlying the effects of MnO2NSs on the tumor microenvironment of A549 lung cancer cells, effectively making up for the deficiency of the study on cellular mechanism of CDT-induced apoptosis of cancer cells. It could aid the development of cancer CDT treatment strategies and help improve the use of nanomaterials in the clinical field.

NIR-II-Responsive CeO2-x@HA Nanotheranostics for Photoacoustic Imaging-Guided Sonodynamic-Enhanced Synergistic Phototherapy.

The therapeutic effect of photothermal therapy (PTT) and photodynamic therapy (PDT) is severely limited because of the shallow tissue penetration depth of the first near-infrared (NIR-I) light. Multifunctional nanotheranostics irradiated by the second near-infrared (NIR-II) light have received wide interest with respect to deeper tissue penetration, and sonodynamic therapy (SDT) synergistic phototherapy can achieve the complete elimination of tumors. Herein, we successfully constructed a single NIR-II light-induced nanotheranostic using cerium oxide (CeO2-x) with abundant oxygen vacancies for photoacoustic imaging-guided SDT-enhanced phototherapy for the first time. CeO2-x with surface crystalline disorder showed extensive NIR-II region absorption and an outstanding photothermal conversion ability. In addition, the CeO2-x layer with numerous oxygen defects can promote the separation of holes and electrons by ultrasound irradiation, which can remarkably enhance the efficacy of phototherapy to achieve high-efficiency tumor ablation. CeO2-x was surface modified with hyaluronic acid (HA) to prepare CeO2-x@HA to allow active tumor targeting efficiency. Both cell and animal experiments confirmed that all-in-one CeO2-x@HA exhibited a high therapeutic efficacy of SDT-enhanced PDT/PTT under 1064 nm laser irradiation, which achieved complete tumor eradication without systemic toxicity. This study significantly broadened the application of NIR-II-responsive CeO2-x for photoacoustic imaging-mediated SDT-enhanced phototherapy to the highly efficient and precise elimination of tumors.

Lysosome-Targeted Gold Nanotheranostics for In Situ SERS Monitoring pH and Multimodal Imaging-Guided Phototherapy.

The integration of surface-enhanced Raman spectrum (SERS) and fluorescence-photoacoustic multimodal imaging in near-infrared photothermal therapy is highly desirable for cancer theranostic. However, typically, gold nanotheranostics usually require an additional modification of fluorophores and complex design refinements. In this work, by integrating surface-modified cysteine-hydroxyl merocyanine (CyHMC) molecules onto AuNRs, a novel lysosome-targeted gold-based nanotheranostics AuNRs-CyHMC that combines the specificity of Raman spectrum, the speed of fluorescence imaging, and deep penetration of photoacoustic imaging was successfully fabricated. Interestingly, fluorescence and Raman signals in this AuNRs-CyHMC system do not interfere, but it has pH-sensitive Raman signals and self-fluorescence localization ability under different excitation wavelengths. Fluorescence co-localization experiments further confirmed the lysosome-targeting ability of AuNRs-CyHMC. Typically, the proposed nanotheranostics were capable of SERS monitoring pH changes in both phosphate-buffered saline and living cells. Meanwhile, in vitro and in vivo experiments revealed that AuNRs-CyHMC possessed excellent fluorescence-photoacoustic performance and could be used for multimodal imaging-guided photothermal therapy. Furthermore, our work implied that gold nanotheranostics can provide great potential for cancer diagnosis and treatment.

Synthesis of MBA-Encoded Silver/Silica Core-Shell Nanoparticles as Novel SERS Tags for Biosensing Gibberellin A3 Based on Au@Fe3O4 as Substrate.

A surface-enhanced Raman scattering (SERS) tag is proposed for high-sensitivity detection of gibberellin A3 (GA3). Silver nanoparticles (AgNPs) were synthesized using citrate reduction. 4-Mercaptobenzoic acid (MBA) was used for the Raman-labeled molecules, which were coupled to the surface of the AgNPs using sulfydryls. MBA was coated with silica using the Stöber method to prevent leakage. GA3 antibodies were attached via the active functional groups N-Hydroxysuccinimide (NHS) and N-Ethyl-N'-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC) to construct a novel immuno-AgNPs@SiO2 SERS tags. The captured SERS substrates were fabricated through Fe3O4 nanoparticles and gold nanoparticles (AuNPs) using chemical methods. These nanoparticles were characterized using ultraviolet-visible spectroscopy (UV-Vis), dynamic light scattering, Raman spectroscopy, transmission electron microscope (TEM), and X-ray diffraction (XRD). This immuno-AgNPs@SiO2 SERS tags has a strong SERS signal based on characterizations via Raman spectroscopy. Based on antigen-antibody reaction, the immuno-Au@Fe3O4 nanoparticles can capture the GA3 and AgNPs@SiO2 SERS tags. Due to the increasing number of captured nanoprobes, the SERS signal from MBA was greatly enhanced, which favored the sensitive detection of GA3. The linear equation for the SERS signal was y = -13635x + 202211 (R2 = 0.9867), and the limit of detection (LOD) was 10-10 M. The proposed SERS tags are also applicable for the detection of other food risk factors.

Selective Probing of Gaseous Ammonia Using Red-Emitting Carbon Dots Based on an Interfacial Response Mechanism.

Solid-state fluorescence sensing is one of the most appealing detection techniques because of its simplicity and convenience in practical operation. Herein, we report the development of a red-emitting carbon dots (RCDs)-based material as a solid-state fluorescence sensor for the selective probing of gaseous ammonia. The RCDs were prepared by a low-cost, one-step carbonization method using sugar cane bagasse as the carbon precursor. The pristine RCDs were then directly coated on polyvinylidene fluoride membrane to produce a new fluorescence sensor capable of selectively distinguishing toxic gaseous ammonia from other analyte vapors through sensitive fluorescence quenching with a low detection limit. More importantly, the interfacial response mechanism occurring on the surface of the RCDs has been studied by X-ray photoelectron spectroscopy, Fourier-transform infrared spectroscopy, and Raman measurements. The results indicate that fluorescence quenching in the RCDs might result from ammonia-induced Michael addition through insertion of N into the C=C group and deprotonation of the carboxyl group. To the best of our knowledge, this is the first report that provides clear insight into the mechanism of surface chemistry on CDs in the solid state.

Near-Infrared-II-Activatable Self-Assembled Manganese Porphyrin-Gold Heterostructures for Photoacoustic Imaging-Guided Sonodynamic-Augmented Photothermal/Photodynamic Therapy.

Porphyrins and their derivatives are widely used as photosensitizers and sonosensitizers in tumor treatment. Nevertheless, their poor water solubility and low chemical stability reduce their singlet oxygen (1O2) yield and, consequently, their photodynamic therapy (PDT) and sonodynamic therapy (SDT) efficiency. Although strategies for porphyrin molecule assembly have been developed to augment 1O2 generation, there is scope for further improving PDT and SDT efficiencies. Herein, we synthesized ordered manganese porphyrin (SM) nanoparticles with well-defined self-assembled metalloporphyrin networks that enabled efficient energy transfer for enhanced photocatalytic and sonocatalytic activity in 1O2 production. Subsequently, Au nanoparticles were grown in situ on the SM surface by anchoring the terminal alkynyl of porphyrin to form plasmonic SMA heterostructures, which showed the excellent near-infrared-II (NIR-II) region absorption and photothermal properties, and facilitated electron-hole pair separation and transfer. With the modification of hyaluronic acid (HA), SMAH heterostructure nanocomposites exhibited good water solubility and were actively targeted to cancer cells. Under NIR-II light and ultrasound (US) irradiation, the SMAH generates hyperthermia, and a large amount of 1O2, inducing cancer cell damage. Both in vitro and in vivo studies confirmed that the SMAH nanocomposites effectively suppressed tumor growth by decreasing GSH levels in SDT-augmented PDT/PTT. Moreover, by utilizing the strong absorption in the NIR-II window, SMAH nanocomposites can achieve NIR-II photoacoustic imaging-guided combined cancer treatment. This work provides a paradigm for enhancing the 1O2 yield of metalloporphyrins to improve the synergistic therapeutic effect of SDT/PDT/PTT.

Label-free fluorescence probe based on structure-switching aptamer for the detection of interferon gamma.

A novel label-free fluorescence probe based on structure-switching aptamer was developed for the detection of interferon-gamma (IFN-γ). In this work, a single stranded DNA (ssDNA) with G-rich sequence (aptamer) was folded into secondary G-quadruplex structures in the presence of Na(+) and Mg(2+), thiazole orange (TO) was then intercalated into the G-quadruplex structures, resulting in a high fluorescence emission. The target combined with its aptamer, disrupts G-quadruplex structure and releases TO, resulting in a reduction of fluorescence. Using IFN-γ as the model target, the proposed fluorescence probe shows a linear range from 3.0 to 120 nM with a detection limit of 2.0 nM. The proposed strategy avoids complicated covalent modifications or chemical labeling, and thus offers advantages of simplicity and cost efficiency.

An autocatalytically-activatable hydrogen peroxide photoacoustic sensor for in situ visualization precise diagnosis and drug intervention tracing in diabetes syndrome.

In situ visualization for the diagnosis of diabetic syndrome and visual monitoring the response to drug treatment is a challenge. Herein, we designed and prepared an autocatalytically-activatable hydrogen peroxide photoacoustic (PA) sensor. We first prepared the FeMoOx nanoparticle with catalase activity, then combined it to 2,2'-azino-bis(3-ethylbenzothi-azoline-6-sulfonic acid) (ABTS) and distearoylphos-phoethanola-mine-polyethylene-glycol (DSPE-PEG) to construct a autocatalytically-activatable PA sensor (FeMoOx@ABTS@DSPE-PEG). In its presence, ABTS can be converted into oxidized ABTS·+ by H2O2. ABTS·+ exhibits strong light absorption in the near-infrared region, and can serve as an ideal contrast agent for PA imaging. H2O2 as a biomarker of oxidative stress response is closely related to the occurrence and development of diabetes mellitus and its complications. Therefore, FeMoOx@ABTS@DSPE-PEG was used as a PA sensor of H2O2 for visual monitoring of the progression of diabetes-induced liver injury and metformin-mediated treatment of diabetes. The autocatalytically-activatable PA sensor developed in this study provides a promising platform for in situ visual diagnosis of diabetes and its syndrome and monitoring the response to therapy.

Near-infrared-II-activatable sulfur-deficient plasmonic Bi2S3-x-Au heterostructures for photoacoustic imaging-guided ultrasound enhanced high performance phototherapy.

Bismuth sulfide is widely used as an n-type semiconductor material in photocatalytic reactions. However, bismuth sulfide has poor absorption in the near-infrared region and low charge separation efficiency, limiting its application in phototherapy and sonodynamic therapy (SDT). In this study, we successfully synthesized an "all-in-one" phototheranostic nanoplatform, namely Bi2S3-x-Au@HA, based on a single second near-infrared (NIR-II) light-responsive Schottky-type Bi2S3-x-Au heterostructure for photoacoustic (PA) imaging-guided SDT-enhanced photodynamic therapy (PDT)/photothermal therapy (PTT). Bi2S3-x-Au@HA exhibits excellent NIR-II plasmonic and photothermal properties, rendering it with NIR-II PA imaging capabilities for accurate diagnosis. Additionally, the high-density sulfur vacancies constructed on the Bi2S3 surface cause it to possess a reduced band gap (1.21 eV) that can act as an electron trap. Using the density functional theory, we confirmed that the light and ultrasound-induced electrons are more likely to aggregate on the Au nanoparticle surface through interfacial self-assembly, which promotes electron-hole separation and enhances photocatalytic activity with increased reactive oxygen species (ROS) generation. With a further modification of hyaluronic acid (HA), Bi2S3-x-Au@HA can selectively target cancer cells through HA and CD44 protein interactions. Both in vitro and in vivo experiments demonstrated that Bi2S3-x-Au@HA effectively suppressed tumor growth through SDT-enhanced PTT/PDT under a single NIR-II laser and ultrasound irradiation with negligible toxicity. Our findings provide a framework for fabricating Schottky-type heterostructures as single NIR-II light-responsive nanotheranostic agents for PA imaging-guided cancer phototherapy.

Metabolomics analysis of MnO2 nanosheets CDT for breast cancer cells and mechanism of cytotoxic action.

Chemodynamic therapy (CDT) has received more and more attention as an emerging therapeutic strategy, especially transition metals with Fenton or Fenton-like activity have good effects in CDT research, manganese dioxide nanosheets (MnO2 NSs) and their complexes have become one of the most favored nanomaterials in CDT of tumors. CDT is mainly based on the role of reactive oxygen species (ROS) in tumor treatment, which have clear chemical properties and produce clear chemical reactions. However, their mechanism of interaction with cells has not been fully elucidated. Here, we performed CDT on mouse breast cancer cells (4T1) based on MnO2 NSs, extracted the metabolites from the 4T1 cells during the treatment, and analyzed the differences in metabolites by using high-resolution liquid chromatography-mass spectrometry (LC-MS). Untargeted metabolomics studies were conducted using the relevant data. This study mainly explored the changes in MnO2 NSs on the metabolite profile of 4T1 cells and their potential impact on tumor therapy, in order to determine the mechanism of action of MnO2 NSs in the treatment of breast cancer. The results of the study showed the presence of 11 different metabolites in MnO2 NSs CDT for 4T1 tumor cells, including phosphoserine, sphingine, phosphocholine, and stearoylcarnitine. These findings provide a deeper understanding of breast cancer treatment, and are beneficial for the further research and clinical application of CDT.

CeO2@CuS@PDA-FA as targeted near-infrared PTT/CDT therapeutic agents for cancer cells.

Single tumor treatment method usually has some defects, which makes it difficult to achieve good therapeutic effect. The ingenious combination of multiple tumor treatment methods on a single nanoplatform to achieve multifunctional treatment can effectively improve the efficiency of treatment. The targeted modification of nanomaterials can augment the precision of nanotherapeutic drugs in tumor treatment. Herein, a multifunctional nanoplatform (CeO2@CuS@PDA-FA) based on cerium dioxide nanoparticles engineered with copper sulfide (CeO2@CuS) has been constructed for synergistic photothermal therapy (PTT) and chemodynamic therapy (CDT). The CeO2@CuS were coated using polydopamine (PDA), and the modification of PDA surface by folic acid, in order to achieve the targeted effect for tumors. The localized hyperthermia induced by PTT can further improve the CDT efficiency of the nanoplatform, leading to a PTT/CDT synergistic effect. The nanoplatform possessed the capability of cancer cell-targeted and achieved better therapeutic efficacyin vitro. This work provided a new strategy for combined multifunctional theranostic platform and shows strong potential in practical applications.

H2O2 Self-Supply and Glutathione Depletion Engineering Nanoassemblies for NIR-II Photoacoustic Imaging of Tumor Tissues and Photothermal-Enhanced Gas Starvation-Primed Chemodynamic Therapy.

The development of tumor microenvironment (TME)-activated nanoassemblies which can produce a photoacoustic (PA) signal and enhance the H2O2 level is critical to achieve accurate diagnosis and highly efficient chemodynamic therapy (CDT). In this study, we developed nanoassemblies consisting of oxygen vacancy titanium dioxide (TiO2-x) surface-constructed copper, sulfur-doped mesoporous organosilica and glucose oxidase (TiO2-x@Cu,S-MONs@GOx, hereafter TMG). We found that highly abundant glutathione (GSH) in the TME nanoassemblies can reduce tetrasulfide bonds and Cu2+ to sulfur ions and Cu+ in the TMG nanoassemblies, respectively, causing the breakage of the tetrasulfide bond and the mesoporous structure collapse, releasing Cu+ ions and TiO2-x nanoparticles, and producing hydrogen sulfide gas, thereby achieving synergistic multimodal tumor treatment through TME-activated NIR-II PA imaging and photothermal-enhanced gas starvation-primed CDT. Therefore, the TMG nanoassemblies form a smart nanoplatform that can serve as an excellent tumor diagnosis-treatment agent by playing an important role in imaging-guided precision diagnosis of cancer and efficient targeting treatment.

Mechanism of Cytotoxic Action of Gold Nanorods Photothermal Therapy for A549 Cell.

Photothermal therapy has developed into an important field of tumor treatment research, and numerous studies have focused on the preparation of photothermal therapeutic agents, tumor targeting, diagnosis, and treatment integration. However, there are few studies on the mechanism of photothermal therapy acting on cancer cells. Here we investigated the metabolomics of lung cancer cell A549 during gold nanorod (GNR) photothermal treatment by high-resolution LC/MS, and several differential metabolites and corresponding metabolic pathways during photothermal therapy were found. The main differential metabolites contained 18-hydroxyoleate, beta-alanopine and cis-9,10-epoxystearic acid, and phosphorylcholine. Pathway analysis also showed metabolic changes involving cutin, suberine, and wax biosynthesis, pyruvate and glutamic acid synthesis, and choline metabolism. Analysis also showed that the photothermal process of GNRs may induce cytotoxicity by affecting pyruvate and glutamate synthesis, normal choline metabolism, and ultimately apoptosis.

Surface-Enhanced Raman Probes Based on Gold Nanomaterials for in vivo Diagnosis and Imaging.

Surface-enhanced Raman scattering (SERS) has received considerable attention from researchers due to its high molecular specificity, high sensitivity, non-invasiveness and multiplexing. Recently, various metal substrates have been exploited for SERS analysis and imaging. Among them, gold nanomaterials are important SERS substrates with outstanding surface plasmon resonance effects, structural adjustability and good biocompatibility, making them widely used in biomedical diagnosis and clinical fields. In this minireview, we discuss the latest progress about the application of gold-based nanomaterials as SERS probes in biomedical research, primarily for in vivo disease diagnosis and imaging. This review mainly includes the basic shapes and morphologies of gold based SERS probes, such as gold nanoparticles (AuNPs), gold nanorods (AuNRs), gold nanostars (AuNSs), as well as other gold nanostructures. Finally, a brief outlook for the future development of SERS technique in the context of efficient diagnostics and therapy guidance is provided. We hope that this review will facilitate the design and future development of surface-enhanced Raman probes based on gold nanomaterials.

NIR-II-responsive AuNRs@SiO2-RB@MnO2 nanotheranostic for multimodal imaging-guided CDT/PTT synergistic cancer therapy.

Specific tumor-responsive capabilities and efficient synergistic therapeutic performance are the keys to effective tumor treatment. Herein, AuNRs@SiO2-RB@MnO2 was developed as a new type of tumor-responsive nanotheranostic for multimodal imaging and synergistic chemodynamic/photothermal therapy. In AuNRs@SiO2-RB@MnO2, the SiO2 layer wraps the AuNRs, providing light absorption in the second near-infrared (NIR-II) region. The SiO2 layer also adsorbs the MnO2 nanosheets, which have Fenton-like activity, resulting in a fluorescent sensing platform based on the fluorescence quenching properties of MnO2 for rhodamine B dye. The fluorescence can be recovered by the consumption of MnO2 by glutathione, which simultaneously produces Mn2+ in the tumor region. The recovery of fluorescence reflects the consumption of glutathione and the increase in Mn2+, which produces hydroxyl radicals via Fenton-like reaction in the tumor microenvironment to realize chemodynamic therapy. Meanwhile, the AuNRs are a good photothermal reagent that can effectively absorb NIR-II light and convert it into heat energy to kill tumor cells via photothermal therapy. The NIR-II absorption performance of the AuNRs provides good photoacoustic imaging and deep photothermal performance, which is favorable for efficient NIR-II photoacoustic imaging-guided photothermal therapy. As a result, the AuNRs@SiO2-RB@MnO2 nanotheranostic exhibits outstanding imaging and synergistic chemodynamic/photothermal therapeutic performance for tumor imaging and treatment.

A full-spectrum responsive B-TiO2@SiO2-HA nanotheranostic system for NIR-II photoacoustic imaging-guided cancer phototherapy.

The second near-infrared (NIR-II) window (1000-1350 nm) usually offers further improved light penetration, a higher maximum permissible exposure (MPE), and a lower background signal. Development of NIR-II optical diagnosis and phototherapy technologies is of great significance for precise, efficient tumor therapy. In this work, a new type of Ti-based targeting agent (B-TiO2@SiO2-HA) nanotheranostic system with strong NIR-II absorption was designed and fabricated for the first time. Oxygen vacancies were formed in B-TiO2 and its band gap was narrowed, resulting in nanotheranostic systems with full-spectrum responses to stimulation with light. The experimental results showed that B-TiO2@SiO2-HA not only can enable high NIR-II photothermal conversion and provide excellent reactive oxygen species (ROS) production capacity, but also can enable high-resolution photoacoustic imaging (PAI) under NIR-II laser irradiation. Moreover, HA modification gives the nanotheranostic systems the useful ability to target high-CD44-expression tumor cells and tissues. In vitro and in vivo experiments demonstrated that B-TiO2@SiO2-HA exhibited a targeted photothermal/photodynamic (PTT/PDT) effect that produced tumor-cell ablation and apoptosis under the guidance of real-time NIR-II PA imaging. B-TiO2@SiO2-HA exhibits precise nanotheranostic potential for PAI-guided tumor-targeting phototherapy.

Triaqua-(1,4,7-triaza-cyclo-nonane-κN,N,N)nickel(II) bromide nitrate.

In the title half-sandwich compound, [Ni(C(6)H(15)N(3))(H(2)O)(3)]Br(NO(3)), the central Ni(II) ion, lying on a threefold rotation axis, is six-coordinated by three amine N atoms from the face-capping triaza macrocycle and three water O atoms in a slightly distorted octa-hedral geometry. In the crystal, O-H⋯O hydrogen bonding and weak O-H⋯Br inter-actions associate the Ni(II) cations and the counter-ions into a three-dimensional supra-molecular network.

A chloroplast-inspired nanoplatform for targeting cancer and synergistic photodynamic/photothermal therapy.

Specific targeting capabilities and effective phototherapeutic functions are the key demands for precise cancer phototherapeutic agents. Herein, a bioinspired nanoplatform composed of Cu(ii)-chlorophyll-hyaluronic acid nanoparticles (Cu(ii)Chl-HA NPs) was developed for targeting cancer and synergistic photodynamic/photothermal therapy. Inspired by the photonic biosystem of the chloroplast, Cu(ii) chlorophyll was used as a photosensitive substituent to covalently connect with a hydrophilic HA tail rather than a natural phytol tail, and this conjugate further assembled into a nanoparticle-like morphology under non-covalent interaction. Time-dependent density functional theory calculations reveal that the Cu(ii) chlorophyll has a much smaller energy gap between an excited singlet and excited triplet, and theoretically leads to rapid electron intersystem crossing that would benefit the PDT effect. In addition, a series of experiments have proven that, under 650 nm laser irradiation, the nanoplatform of Cu(ii)Chl-HA can produce a high amount of singlet oxygen and exhibit an outstanding photothermal conversion capability. More interestingly, owing to the specific interactions between the HA component and the CD44 receptor on the cell membrane, the HA tails impart Cu(ii)Chl-HA NPs an excellent receptor-mediated targeting performance toward CD44-overexpressing cancer cells. Based on these features, the nanoplatform of Cu(ii)Chl-HA NPs presents active targeting and outstanding dual modality synergistic PDT/PTT performance of cancer both in vitro and in vivo. Thus, this work opens up a new strategy to fabricate a bioinspired multifunctional cancer phototherapy nanoplatform.

Receptor-Mediated and Tumor-Microenvironment Combination-Responsive Ru Nanoaggregates for Enhanced Cancer Phototheranostics.

Although phototherapy has been considered as an emerging and promising technology for cancer therapy, its therapeutic specificity and efficacy are severely limited by nonspecific uptake by normal tissues, tumor hypoxia, and so on. Herein, combination-responsive strategy (CRS) is applied to develop one kind of hyaluronic acid-hybridized Ru nanoaggregates (HA-Ru NAs) for enhanced cancer phototherapy via the reasonable integration of receptor-mediated targeting (RMT) and tumor-microenvironment responsiveness (TMR). In this nanosystem, the HA component endows HA-Ru NAs with RMT characteristic to selectively recognize CD44-overexpressing cancer cells, whereas the Ru nanocomponent makes HA-Ru NAs have TMR therapy activity. Specially, the Ru nanocomponent not only has near-infrared-mediated photothermal and photodynamic functions but also can catalyze H2O2 in tumor tissue to produce O2 for the alleviation of tumor hypoxia and toxic •OH for chemodynamic therapy. Benefitting from these, HA-Ru NAs can be considered as a promising kind of CRS nanoplatforms for synergistic photothermal/photodynamic/chemodynamic therapies of cancer, which will not only effectively improve the phototherapeutic specificity and efficacy but also simplify the therapeutic nanosystems. Meanwhile, HA-Ru NAs can serve as a photoacoustic and computed tomography imaging contrast agent to monitor tumors. Such CRS nanoplatforms hold significant potential in improving therapeutic specificity and efficacy for enhanced cancer phototheranostics.