Magnetotactic Bacteria AMB-1 with Active Deep Tumor Penetrability for NIR-II Photothermal Tumor Therapy.

The complex tumor structure and microenvironment such as abnormal tumor vasculature, dense tumor matrix, and elevated interstitial fluid pressure greatly hinder the penetration and retention of therapeutic agents in solid tumors. The development of an advanced method for robust penetration and retention of therapeutic agents in tumors is of great significance for efficient tumor treatments. In this work, we demonstrated that magnetotactic bacteria AMB-1 with hypoxic metabolism characteristics can actively penetrate the tumor to selectively colonize deep hypoxic regions, which emerge as a promising intelligent drug carrier. Furthermore, AMB-1 presents intrinsic second near-infrared (NIR-II) photothermal performance that can efficiently convert a 1064 nm laser into heat for tumor thermal ablation. We believe that our investigations not only develop a novel bacteria-based photothermal agent but also provide useful insights for the development of advanced tumor microbial therapies.

Dual-Responsive Turn-On T1 Imaging-Guided Mild Photothermia for Precise Apoptotic Cancer Therapy.

Apoptosis has gained increasing attention in cancer therapy as an intrinsic signaling pathway, which leads to minimal leakage of waste products from a dying cell to neighboring normal cells. Among various stimuli to trigger apoptosis, mild hyperthermia is attractive but confronts limitations of non-specific heating and acquired resistance from elevated expression of heat shock proteins. Here, a dual-stimulation activated turn-on T1 imaging-based nanoparticulate system (DAS) is developed for mild photothermia (≈43 °C)-mediated precise apoptotic cancer therapy. In the DAS, a superparamagnetic quencher (ferroferric oxide nanoparticles, Fe3 O4 NPs) and a paramagnetic enhancer (Gd-DOTA complexes) are connected via the N6-methyladenine (m6 A)-caged, Zn2+ -dependent DNAzyme molecular device. The substrate strand of the DNAzyme contains one segment of Gd-DOTA complex-labeled sequence and another one of HSP70 antisense oligonucleotide. When the DAS is taken up by cancer cells, overexpressed fat mass and obesity-associated protein (FTO) specifically demethylates the m6 A group, thereby activating DNAzymes to cleave the substrate strand and simultaneously releasing Gd-DOTA complex-labeled oligonucleotides. The restored T1 signal from the liberated Gd-DOTA complexes lights up the tumor to guide the location and time of deploying 808 nm laser irradiation. Afterward, locally generated mild photothermia works in concert with HSP70 antisense oligonucleotides to promote apoptosis of tumor cells. This highly integrated design provides an alternative strategy for mild hyperthermia-mediated precise apoptotic cancer therapy.

A Telomerase-Activated Magnetic Resonance Imaging Probe for Consecutively Monitoring Tumor Growth Kinetics and In Situ Screening Inhibitors.

Telomerase has long been considered as a biomarker for cancer diagnosis and a therapeutic target for drug discovery. Detecting telomerase activity in vivo could provide more direct information of tumor progression and response to drug treatment, which, however, is hampered by the lack of an effective probe that can generate an output signal without a tissue penetration depth limit. In this study, using the principle of distance-dependent magnetic resonance tuning, we constructed a telomerase-activated magnetic resonance imaging probe (TAMP) by connecting superparamagnetic ferroferric oxide nanoparticles (SPFONs) and paramagnetic Gd-DOTA (Gd(III) 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) complexes via telomerase-responsive DNA motifs. Upon telomerase-catalyzed extension of the primer in TAMP, Gd-DOTA-conjugated oligonucleotides can be liberated from the surface of SPFONs through a DNA strand displacement reaction, restoring the T1 signal of the Gd-DOTA for a direct readout of the telomerase activity. Here we show that, by tracking telomerase activity, this probe provides consistent monitoring of tumor growth kinetics during progression and in response to drug treatment and enables in situ screening of telomerase inhibitors in whole-animal models. This study provides an alternative toolkit for cancer diagnosis, treatment response assessment, and anticancer drug screening.

Switchable ROS Scavenger/Generator for MRI-Guided Anti-Inflammation and Anti-Tumor Therapy with Enhanced Therapeutic Efficacy and Reduced Side Effects.

Photosensitizer in photodynamic therapy (PDT)  accumulates in both tumor and adjacent normal tissue due to low selective biodistribution, results in undesirable side effect with limited clinic application. Herein, an intelligent nanoplatform is reported that selectively acts as reactive oxygen species (ROS) scavenger in normal tissue but as ROS generator in tumor microenvironment (TME) to differentially control ROS level in tumor and surrounding normal tissue during PDT. By down-regulating the produced ROS with dampened cytokine wave in normal tissue after PDT, the nanoplatform reduces the inflammatory response of normal tissue in PDT, minimizing the side effect and tumor metastasis in PDT. Alternatively, the nanoplatform switches from ROS scavenger to generator through the glutathione (GSH) responsive degradation in TME, which effectively improves the PDT efficacy with reduced GSH level and amplified oxidative stress in tumor. Simultaneously, the released Mn ions provide real-time and in situ signal change of magnetic resonance imaging (MRI) to monitor the reversal process of catalysis activity and achieve accurate tumor diagnosis. This TME-responsive ROS scavenger/generator with activable MRI contrast may provide a new dimension for design of next-generation PDT agents with precise diagnosis, high therapeutic efficacy, and low side effect.

Magnetotactic bacteria AMB-1 with active deep tumor penetrability for magnetic hyperthermia of hypoxic tumors.

Tumor hypoxia is a great physiological barrier for tumor treatment. The development of efficient detection and treatment methods for tumor hypoxia has great scientific and clinical significance. In this work, we investigated the potential of magnetotactic bacteria AMB-1 for magnetic resonance imaging (MRI)-guided magnetic hyperthermia treatment of hypoxic tumors. Our investigations reveal that AMB-1 bacteria can selectively migrate to the hypoxic regions of solid tumors due to their anaerobic characteristics, showing active deep tumor penetrability. Moreover, AMB-1 bacteria exhibit high MRI contrast and magnetic heating performances because of the excellent magnetic performance of their magnetosomes. In vivo studies demonstrate that AMB-1 can not only generate T2-weighted contrast signals in tumor tissue, but also efficiently ablate hypoxic solid tumors through the magnetic hyperthermia effect. We believe that this novel microbial therapy can be a potential weapon for hypoxic tumor treatment.

Engineering manganese ferrite shell on iron oxide nanoparticles for enhanced T1 magnetic resonance imaging.

Doping Mn (II) ions into iron oxide (IO) as manganese ferrite (MnIO) has been proved to be an effective strategy to improve T1 relaxivity of IO nanoparticle in recent years; however, the high T2 relaxivity of MnIO nanoparticle hampers its T1 contrast efficiency and remains a hurdle when developing contrast agent for early and accurate diagnosis. Herein, we engineered the interfacial structure of IO nanoparticle coated with manganese ferrite shell (IO@MnIO) with tunable thicknesses. The Mn-doped shell significantly improve the T1 contrast of IO nanoparticle, especially with the thickness of ∼0.8 nm. Compared to pristine IO nanoparticle, IO@MnIO nanoparticle with thickness of ∼0.8 nm exhibits nearly 2 times higher T1 relaxivity of 9.1 mM-1s-1 at 3 T magnetic field. Moreover, exclusive engineering the interfacial structure significantly lower the T2 enhancing effect caused by doped Mn (II) ions, which further limits the impairing of increased T2 relaxivity to T1 contrast imaging. IO@MnIO nanoparticles with different shell thicknesses reveal comparable T1 relaxation rates but obvious lower T2 relaxivities and r2/r1 ratios to MnIO nanoparticles with similar sizes. The desirable T1 contrast endows IO@MnIO nanoparticle to provide sufficient signal difference between normal and tumor tissue in vivo. This work provides a detailed instance of interfacial engineering to improve IO-based T1 contrast and a new guidance for designing effective high-performance T1 contrast agent for early cancer diagnosis.

Improving the sensitivity of T1 contrast-enhanced MRI and sensitive diagnosing tumors with ultralow doses of MnO octahedrons.

Rationale: Sensitive and accurate imaging of cancer is essential for early diagnosis and appropriate treatment. For generally employed magnetic resonance imaging (MRI) in clinic, comprehending how to enhance the contrast effect of T1 imaging is crucial for improving the sensitivity of cancer diagnosis. However, there is no study ever to reveal the clear mechanism of how to enhance the effect of T1 imaging and accurate relationships of influencing factors. Herein, this study aims to figure out key factors that affect the sensitivity of T1 contrast-enhanced MRI (CE-MRI), thereby to realize sensitive detection of tumors with low dose of CAs. Methods: Manganese oxide (MnO) nanoparticles (NPs) with various sizes and shapes were prepared by thermal decomposition. Factors impacting T1 CE-MRI were investigated from geometric volume, surface area, crystal face to r2/r1 ratio. T1 CE-MR imaging of liver, hepatic and subcutaneous tumors were conducted with MnO NPs of different shapes. Results: The surface area and occupancy rate of manganese ions have positive impacts on the sensitivity of T1 CE-MRI, while volume and r2/r1 ratio have negative effects. MnO octahedrons have a high r1 value of 20.07 mM-1s-1 and exhibit an excellent enhanced effect in liver T1 imaging. ZDS coating facilitates tumor accumulation and cellular uptake, hepatic and subcutaneous tumors could be detected with MnO octahedrons at an ultralow dose of 0.4 mg [Mn]/kg, about 1/10 of clinical dose. Conclusions: This work is the first quantitative study of key factors affecting the sensitivity of T1 CE-MRI of MnO nanoparticles, which can serve as a guidance for rational design of high-performance positive MRI contrast agents. Moreover, these MnO octahedrons can detect hepatic and subcutaneous tumors with an ultralow dose, hold great potential for sensitive and accurate diagnosis of cancer with lower cost, less dosages and side effects in clinic.

Magnetothermally Triggered Free-Radical Generation for Deep-Seated Tumor Treatment.

Tumor hypoxia and the tissue penetration limitation of excitation light hamper the widespread clinical use of photodynamic therapy. The development of new therapeutic strategies that can generate oxygen-independent free radicals without penetration depth limitation is of great demand. Herein, a novel magnetothermodynamic strategy for deep-seated tumor therapy is reported. In this system, a radical initiator (AIPH) was loaded into porous hollow iron oxide nanoparticles (PHIONs). Under the induction of an alternating magnetic field (AMF), PHIONs can generate heat to trigger the release and decomposition of AIPH, resulting in the generation of oxygen-independent alkyl radicals. The resulting alkyl radicals can effectively kill cancer cells under hypoxic conditions. More importantly, this magnetothermally triggered free-radical generator exhibits significant therapeutic efficacy for orthotopic liver tumors in a rat model. This magnetothermodynamic therapy strategy with the advantages of oxygen independence and no limitation of penetration depth holds great promise in deep-seated solid tumor treatment.

Boron Quantum Dots for Photoacoustic Imaging-Guided Photothermal Therapy.

Photothermal therapy is a new type of tumor therapy with great potential. An ideal photothermal therapy agent should have high photothermal conversion effect, low biological toxicity, and degradability. The development of novel photothermal therapy agents with these properties is of great demand. In this study, we synthesized boron quantum dots (BQDs) with an ultrasmall hydrodynamic diameter. Both in vitro and in vivo studies show that the as-synthesized BQDs have good biological safety, high photoacoustic imaging performance, and photothermal conversion ability, which can be used for photoacoustic imaging-guided photothermal agents for tumor treatment. Our investigations confirm that the BQDs hold great promise in tumor theranostic applications.

Evaluation of the Therapeutic Effect of Magneto-Nanomicelles Based on Magneto-Thermal and Photo-Thermal Therapy.

In this study, we investigated the hyperthermia efficiency of magnetic hyperthermia therapy (MHT), photo-thermal therapy (PTT), and the combination of both techniques by employing SPIO-based magneto-nanomicelles as the heating agents. Magneto-nanomicelles in aqueous suspension were exposed to 808-nm laser irradiation (PTT mode), alternating magnetic field (MHT mode), and both modalities (DUAL mode). All the three methods can offer effective temperature increases (above 20 °C). DUAL-mode resulted in an approximately 2-fold increase in heating efficiency (36 °C) compared with PTT or MHT alone. For in vivo experiments, a total of 24 Lewis carcinoma-bearing mice were randomly divided into four groups: the control group (no therapy), PTT, MHT, and DUAL group. In the three therapy groups, magneto-nanomicelles were injected into the tumor and the corresponding treatment measures were performed every other day for a total of three times each. MRI scans were used to calculate tumor volume after each treatment. One-way analysis of variance (ANOVA) was employed to compare the curative effect of different treatment groups. Compared with the control group, PTT, MHT, and DUAL groups all showed a significant inhibitory effect on tumor volume (P < 0.05). In the DUAL group, the mean tumor volume was smaller than that of the PTT or the MHT group. Our work demonstrated that hyperthermia using SPIO-based magnetonanomicelles has a remarkable suppressive effect in anticancer therapy. Moreover, the combined model of hyperthermia in vivo can achieve synthetic effects with shorter healing time by using the same magneto-nanomicelles.

Artificial chimeric exosomes for anti-phagocytosis and targeted cancer therapy.

Development of exosome-based delivery systems is still facing some formidable challenges, including the lack of standardized isolation and purification methods, non-large-scale production and low drug-loading efficiency. Inspired by biomimetic technologies, we turned to the design of artificial chimeric exosomes (ACEs) constructed by integrating cell membrane proteins from multiple cell types into synthetic phospholipid bilayers. For benchmarking, hybrid membrane proteins derived from red blood cells (RBCs) and MCF-7 cancer cells were selected as models. The resulting ACEs were engineered much like "Emperor Qin's Terra-Cotta Warriors", simultaneously equipped with armor (anti-phagocytosis capability from RBCs) and dagger-axes (homologous targeting ability from cancer cells). ACEs demonstrated higher tumor accumulation, lower interception and better antitumor therapeutic effect than plain liposomes in vivo, alongside large-scale standardized preparation, stable structure, high drug-loading capacity and custom-tailored functionality, highlighting the suitability of ACEs as promising alternatives of exosomes in clinical applications.

Near-Infrared Light-Triggered Sulfur Dioxide Gas Therapy of Cancer.

The exploitation of gas therapy platforms holds great promise as a "green" approach for selective cancer therapy, however, it is often associated with some challenges, such as uncontrolled or insufficient gas generation and unclear therapeutic mechanisms. In this work, a gas therapy approach based on near-infrared (NIR) light-triggered sulfur dioxide (SO2) generation was developed, and the therapeutic mechanism as well as in vivo antitumor therapeutic efficacy was demonstrated. A SO2 prodrug-loaded rattle-structured upconversion@silica nanoparticles (RUCSNs) was constructed to enable high loading capacity without obvious leakage and to convert NIR light into ultraviolet light so as to activate the prodrug for SO2 generation. In addition, SO2 prodrug-loaded RUCSNs showed high cell uptake, good biocompatibility, intracellular tracking ability, and high NIR light-triggered cytotoxicity. Furthermore, the cytotoxic SO2 was found to induce cell apoptosis accompanied by the increase of intracellular reactive oxygen species levels and the damage of nuclear DNA. Moreover, efficient inhibition of tumor growth was achieved, associated with significantly prolonged survival of mice. Such NIR light-triggered SO2 therapy may provide an effective strategy to stimulate further development of synergistic cancer therapy platforms.

Iron phosphide nanoparticles as a pH-responsive T 1 contrast agent for magnetic resonance tumor imaging.

In this work, the potential of FeP nanoparticles as a pH-responsive T 1 contrast agent was investigated. The FeP nanoparticles have good biocompatibility and can significantly amplify T 1 magnetic resonance signals in response to the acidic microenvironment of solid tumors, holding great promise in serving as an acid-activatable T 1 contrast agent for tumor imaging.

Black Phosphorus Quantum Dots with Renal Clearance Property for Efficient Photodynamic Therapy.

Black phosphorus (BP) nanomaterials have emerged as rapidly rising stars in the field of nanomedicine. In this work, BP quantum dots (BPQDs) are synthesized and their potential as photosensitizers is investigated for the first time. The BPQDs present good stability in physiological medium and no appreciable cytotoxicity. More importantly, the BPQDs can be rapidly eliminated from the body in their intact form via renal clearance due to their ultrasmall hydrodynamic diameter (5.4 nm). Both in vitro and in vivo studies indicate that the BPQDs have excellent photodynamic effect under light irradiation that can effectively generate reactive oxygen species to kill cancer cells. The BPQDs thus can serve as biocompatible and powerful photosensitizers for efficient photodynamic therapy.

Copper Manganese Sulfide Nanoplates: A New Two-Dimensional Theranostic Nanoplatform for MRI/MSOT Dual-Modal Imaging-Guided Photothermal Therapy in the Second Near-Infrared Window.

Multifunctional nanoplatforms with integrated diagnostic and therapeutic functions have attracted tremendous attention. Especially, the second near-infrared (NIR-II) light response-based nanoplatforms hold great potential in cancer theranostic applications, which is because the NIR-II window provides larger tissue penetration depth and higher maximum permissible exposure (MPE) than that of the well-studied first near-infrared (NIR-I) window. Herein, we for the first time present a two-dimensional (2D)-nanoplatform based on Cu2MnS2 nanoplates (NPs) for magnetic resonance imaging (MRI)/multispectral optoacoustic tomography (MSOT) dual-modal imaging-guided photothermal therapy (PTT) of cancer in the NIR-II window. Methods: Cu2MnS2 NPs were synthesized through a facile and environmentally friendly process. A series of experiments, including the characterization of Cu2MnS2 NPs, the long-term toxicity of Cu2MnS2 NPs in BALB/c nude mice, the applications of Cu2MnS2 NPs for in vitro and in vivo MRI/MSOT dual-modal imaging and NIR-II PTT of cancer were carried out. Results: The as-synthesized Cu2MnS2 NPs exhibit low cytotoxicity, excellent biocompatibility as well as high photothermal conversion efficiency (~49.38%) and outstanding photostability. Together with their good T1-shortening effect and strong absorbance in the NIR-I and NIR-II region, the Cu2MnS2 NPs display high-contrast imaging performance both in MRI and MSOT (900 nm laser source). Moreover, the subsequent in vitro and in vivo results demonstrate that the Cu2MnS2 NPs possess excellent PTT efficacy under 1064 nm laser irradiation with a low power density (0.6 W cm-2). In addition, the detailed long-term toxicity studies further confirming the safety of Cu2MnS2 NPs in vivo. Conclusion: We have developed a new 2D Cu2MnS2 NPs as multifunctional theranostic agents for MRI/MSOT dual-modal imaging-guided PTT of cancer in the NIR-II window. Such biocompatible Cu2MnS2 NPs might provide a new perspective for exploring new 2D-based nanoplatforms with improved properties for clinical applications in the future.

Bioinspired "Active" Stealth Magneto-Nanomicelles for Theranostics Combining Efficient MRI and Enhanced Drug Delivery.

The mononuclear phagocyte system (MPS) with key roles in recognition and clearance of foreign particles, is a major constraint to nanoparticle-based delivery systems. The desire to improve the delivery efficiency has prompted the search for stealthy long-circulating nanoplatforms. Herein, we design an antiphagocytic delivery system with "active" stealth behavior for cancer theranostics combining efficient MRI and enhanced drug delivery. We modify self-peptide, a synthetic peptide for active immunomodulation, to biodegradable poly(lactide-glycolide)-poly(ethylene glycol) (PLGA-PEG), then utilize the self-assembly properties of PLGA-PEG to form nanomicelles that encapsulating iron oxide (IO) nanoparticles and anticancer drug paclitaxel (PTX). Through the interaction of self-peptide with the receptor SIRPα, which is expressed on phagocytes, the as-prepared nanomicelles can disguise as "self" to avoid being recognized as foreign particles by MPS, leading to improved blood circulation time and delivery efficiency. Compared to the "passive" stealth effect generating by PEG or zwitterionic polymers that only passively delay the physisorption of serum proteins to nanocarriers, the "active self" nanomicelles can more efficiently inhibit the MPS-mediated immune clearance and reduce "accelerated blood clearance" phenomenon. Furthermore, this one-step clustering of IO nanoparticles and loading of PTX endow the resulted magneto-nanomicelles with enhanced T2 MRI contrast performance and antitumor effect. We believe that this study provides a novel approach in designing of efficient stealth antiphagocytic delivery systems that resisting the MPS-mediated clearance for cancer theranostics.

Polyphenol-Inspired Facile Construction of Smart Assemblies for ATP- and pH-Responsive Tumor MR/Optical Imaging and Photothermal Therapy.

Smart assemblies have attracted increased interest in various areas, especially in developing novel stimuli-responsive theranostics. Herein, commercially available, natural tannic acid (TA) and iron oxide nanoparticles (Fe3 O4 NPs) are utilized as models to construct smart magnetic assemblies based on polyphenol-inspired NPs-phenolic self-assembly between NPs and TA. Interestingly, the magnetic assemblies can be specially disassembled by adenosine triphosphate, which shows a stronger affinity to Fe3 O4 NPs than that of TA and partly replaces the surface coordinated TA. The disassembly can further be facilitated by the acidic environment hence causing the remarkable change of the transverse relaxivity and potent "turn-on" of fluorescence (FL) signals. Therefore, the assemblies for specific and sensitive tumor magnetic resonance and FL dual-modal imaging and photothermal therapy after intravenous injection of the assemblies are successfully employed. This work not only provides understandings on the self-assembly between NPs and polyphenols, but also will open new insights for facilely constructing versatile assemblies and extending their biomedical applications.

Manganese-iron layered double hydroxide: a theranostic nanoplatform with pH-responsive MRI contrast enhancement and drug release.

Stimuli-responsive theranostic platforms are highly desirable for efficient cancer treatment because of their improved specificity and sensitivity. In this work, we report a manganese-iron layered double hydroxide (MnFe-LDH) for the first time and demonstrate that it can serve as a pH-responsive nanoplatform for cancer theranostics. The MnFe-LDH can respond to the acidic microenvironment of solid tumors to release paramagnetic Mn2+ and Fe3+ ions, resulting in great enhancement of the T1 MRI contrast of the tumor area. In addition, the layered structure enables MnFe-LDH to effectively deliver chemotherapeutic drugs in a pH-controlled manner, and therefore it can simultaneously inhibit the growth of solid tumors. We believe that this novel MnFe-LDH with pH-responsive property holds great promise in cancer theranostic applications.

Gadolinium oxysulfide-coated gold nanorods with improved stability and dual-modal magnetic resonance/photoacoustic imaging contrast enhancement for cancer theranostics.

Gold nanorods (GNRs) are emerging as a promising nanoplatform for cancer theranostics because of their unique optical properties. However, they still suffer from many limitations, such as high cytotoxicity, low thermodynamic and biological stability, and a tedious process for integrating other imaging modalities, for further practical biomedical applications. In this work, a strategy by one-step coating of Gd2O2S around GNRs is reported to address these limitations of GNRs. After the coating of the Gd2O2S shell, the as-fabricated Gd2O2S coated GNRs (GNRs@Gd2O2S) show enhanced biocompatibility and photostability, and tunable localized surface plasmon resonance. The strong absorption in the near-infrared region renders GNRs@Gd2O2S outstanding photoacoustic imaging and photothermal therapy capabilities. Moreover, owing to the T1 shortening ability of Gd2O2S, the GNRs@Gd2O2S also show an excellent T1 MRI contrast performance. The GNRs@Gd2O2S thus can serve as a versatile nanoplatform for cancer theranostics combining dual-modal imaging and photothermal therapy.

Facile Phase Transfer and Surface Biofunctionalization of Hydrophobic Nanoparticles Using Janus DNA Tetrahedron Nanostructures.

Hydrophobic nanoparticles have shown substantial potential for bioanalysis and biomedical applications. However, their use is hindered by complex phase transfer and inefficient surface modification. This paper reports a facile and universal strategy for phase transfer and surface biofunctionalization of hydrophobic nanomaterials using aptamer-pendant DNA tetrahedron nanostructures (Apt-tet). The Janus DNA tetrahedron nanostructures are constructed by three carboxyl group modified DNA strands and one aptamer sequence. The pendant linear sequence is an aptamer, in this case AS1411, known to specifically bind nucleolin, typically overexpressed on the plasma membranes of tumor cells. The incorporation of the aptamers adds targeting ability and also enhances intracellular uptake. Phase-transfer efficiency using Apt-tet is much higher than that achieved using single-stranded DNA. In addition, the DNA tetrahedron nanostructures can be programmed to permit the incorporation of other functional nucleic acids, such as DNAzymes, siRNA, or antisense DNA, allowing, in turn, the construction of promising theranostic nanoagents for bioanalysis and biomedical applications. Given these unique features, we believe that our strategy of surface modification and functionalization may become a new paradigm in phase-transfer-agent design and further expand biomedical applications of hydrophobic nanomaterials.