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Optical voltage sensors with the ability to monitor neuronal activities are invaluable tools for studying information processing of the brain. However, the current genetically encoded voltage indicators usually require high-power visible light for excitation and are limited to genetically addressable model animals. Here, we report a near-infrared (NIR)-excited nongenetic voltage nanosensor that achieves stable recording of neuronal membrane potential in intact animals. The nanosensor is composed of a Förster resonance energy transfer (FRET) pair, the outer membrane-anchored upconversion nanoparticle (UCNP), and the membrane-embedded dipicrylamine (DPA). The negative charge of DPA allows membrane potential fluctuation to affect the distance between the DPA and UCNP, therefore changing the FRET efficiency. Consequently, the emission intensity of the nanosensor can report the membrane potential. Using the nanosensor, we monitor not only electrically evoked changes in the membrane potential of cultured cells but also sensory responses of neurons in intact zebrafish and brain state-modulated subthreshold activities of cortical neurons in intact mice.

Photodynamic therapy (PDT) has become widely accepted and utilized for tumor therapy. Considering the natural shortcomings (e.g., lack of an ideal photosensitizer and limited light penetration depth), lanthanide doped upconversion nanoparticles (Ln-doped UCNP), which can be excited with near-infrared light (NIR) for UV/visible/NIR upconversion luminescence (UCL) emissions, show great potential for augmenting biological treatment with PDT for solid tumors and for visual bioimaging of disease lesions. This review summarizes the basic concepts and important influence factors on PDT, the optimized construction of UCNP-based photosensitizer (UCNP-PS) systems, and some representative examples of UCNP-based PDT (UC-PDT) applications in combination with other traditional therapy methods, such as chemotherapy, radiotherapy, photothermal therapy (PTT) and gene therapy. This review will provide guidance for the design and fabrication of future new UCNP-based nanocomposites for synergistic UC-PDT therapy.

The "partial matching" between upconversion nanoparticle (UCNP) emission and absorption by photosensitizers (PSs) often leads to a theoretically reduced therapeutic efficiency in UC-based photodynamic therapy (PDT) strategies in which the chosen PSs have limited capabilities and are unable to utilize all the near-infrared-upconverted light. In this study, needle-like SnWO4 nanocrystals (SWs) with a broad UV-vis absorption region were synthesized to solve the problem. After covalent conjugation with UCNPs, all the UCNP-emitted light was effectively absorbed by SWs, triggering the type-I PDT process to activate ROS maxima. The unique nanostructure of the as-formed UCNP-SnWO4 nanohybrids (USWs) also enhanced the receiving light intensities of SW, which further boosted the antitumor efficacy. Meanwhile, the strong X-ray attenuation capacity of both tungsten and tin elements qualified the USWs as excellent radio-sensitizers for radiotherapy (RT) enhancement, which played a complementary role with PDT treatment because PDT-mediated induction arrested the cells in the G0-G1 cell cycle phase, and RT was more damaging toward cells in the G2/M phase. The remarkably enhanced UC-PDT/RT efficiency of USWs was next validated in vitro and in vivo, and the combined NIR light and ionizing irradiation treatment completely suppressed tumor growth, revealing its great potential as an efficient anticancer therapeutic agent against solid tumors.

Hypoxia development in tumor is closely associated with its increased aggressiveness and strong resistance to therapy, leading to the poor prognosis in several cancer types. Clinically, invasive oxygen microelectrode and high dosage radiotherapy are often utilized to accurately detect and effectively fight hypoxia. Recently, however, there has been a surge of interdisciplinary research aiming at developing functional molecules and nanomaterials that can be used to noninvasively image and efficiently treat hypoxic tumors. In this review, we will provide an overview of the reports published to date on the imaging and therapy of hypoxic tumors. First, we will present the design concepts and engineering of various hypoxia-responsive probes that can be applied to image hypoxia noninvasively, in an order of fluorescent imaging, positron emission tomography, magnetic resonance imaging, and photoacoustic imaging. Then, we will summarize the up-to-date functional nanomaterials which can be used for the effective treatments of tumor hypoxia. The well-established chemical functions of these elaborately designed nanostructures will enable clinicians to adopt specific treatment concepts by overcoming or even utilizing hypoxia. Finally, challenges and future perspectives facing the researchers in the field will be discussed.

A material that rapidly absorbs molecular oxygen (known as an oxygen scavenger or deoxygenation agent (DOA)) has various industrial applications, such as in food preservation, anticorrosion of metal and coal deoxidation. Given that oxygen is vital to cancer growth, to starve tumours through the consumption of intratumoral oxygen is a potentially useful strategy in fighting cancer. Here we show that an injectable polymer-modified magnesium silicide (Mg2Si) nanoparticle can act as a DOA by scavenging oxygen in tumours and form by-products that block tumour capillaries from being reoxygenated. The nanoparticles are prepared by a self-propagating high-temperature synthesis strategy. In the acidic tumour microenvironment, the Mg2Si releases silane, which efficiently reacts with both tissue-dissolved and haemoglobin-bound oxygen to form silicon oxide (SiO2) aggregates. This in situ formation of SiO2 blocks the tumour blood capillaries and prevents tumours from receiving new supplies of oxygen and nutrients.

Magnetic resonance imaging (MRI) is a highly valuable non-invasive imaging tool owing to its exquisite soft tissue contrast, high spatial resolution, lack of ionizing radiation, and wide clinical applicability. Contrast agents (CAs) can be used to further enhance the sensitivity of MRI to obtain information-rich images. Recently, extensive research efforts have been focused on the design and synthesis of high-performance inorganic nanoparticle-based CAs to improve the quality and specificity of MRI. Herein, the basic rules, including the choice of metal ions, effect of electron motion on water relaxation, and involved mechanisms, of CAs for MRI have been elucidated in detail. In particular, various design principles, including size control, surface modification (e.g. organic ligand, silica shell, and inorganic nanolayers), and shape regulation, to impact relaxation of water molecules have been discussed in detail. Comprehensive understanding of how these factors work can guide the engineering of future inorganic nanoparticles with high relaxivity. Finally, we have summarized the currently available strategies and their mechanism for obtaining high-performance CAs and discussed the challenges and future developments of nanoparticulate CAs for clinical translation in MRI.

As a distinct feature of Alzheimer's disease (AD), the presence of excess metal ions in the brain is most probably one of the main causative factors for the aggregation of β-Amyloid (Aβ) proteins. The design of nanoprobes for detection and control of ion concentrations will be of great importance in predicting the progression of AD and simultaneously providing effective treatments. Herein, we report the design and synthesis of a novel yet smart nanoprobe that can sensitively detect the Cu 2+ concentration and concurrently capture Cu 2+ both in vitro and in vivo . The designed nanoprobe (UCHQ) combines two main components: upconversion nanoparticles (UCNPs) used for the detection and upconversion luminescence (UCL) imaging of Cu 2+ upon 980 nm exposure and the chelator 8-hydroxyquinoline-2-carboxylic acid (HQC) used for chelating Cu 2+ and AD therapy. The results show that the emission intensity of UCHQ is highly dependent on the Cu 2+ concentrations due to the luminescence resonance energy transfer (LRET) from UCNPs to HQC-bonded Cu 2+ . Fascinatingly, the as-constructed UCHQs could be used for UCL imaging of Aβ both in cells and AD mice. Most importantly, UCHQs could not only inhibit the Aβ aggregation-induced apoptosis via capturing overmuch Cu 2+ but also accelerate the nontoxic structural transformation of Aβ.

Following the "detect-to-treat" strategy, by biological engineering, the emerging upconversion nanoparticles (UCNPs) have become one of the most promising inorganic nanomedicines, and their biomedical applications have gradually shifted from multimodal tumor imaging to highly efficient cancer therapy. The past few years have witnessed a three-stage development of UCNP-based nanomedicines. On one hand, UCNPs can optimize each clinical treatment tool (chemotherapy, photodynamic therapy (PDT), radiotherapy (RT)) by controlled drug delivery/release, near-infrared (NIR)-excited deep PDT, and radiosensitization, respectively, all of which contribute greatly to the optimized treatment efficacy along with minimized side effects. On the other hand, several individual treatments can be "smartly" integrated into a single UCNP-based nanotheranostic system for multimodal synergetic therapy, which can further improve the overall therapeutic effectiveness. Especially, UCNPs provide more-effective strategies for overcoming tumor hypoxia, thus leading to an ideal treatment efficacy for complete eradication of solid tumors. Finally, the critical issues regarding the future development of UCNPs are discussed to promote the clinic-translational applications of UCNP-based nanomedicines, as well as realization of our "one drug fits all" dream.

In recent decades, extensive attention has been paid to developing anatomic and functional imaging contrast agents that could provide a wealth of complementary bioimaging information. Among them, dual-mode nanoprobes that combine anatomic magnetic resonance imaging (MRI) with functional fluorescent imaging have been mostly used for separated imaging. However, the lack of a machine for simultaneous dual-mode imaging greatly limits further clinical application. One effective strategy is to rationally design MRI contrast agents that own both anatomic and functional MR imaging capability on a single MRI machine, which is highly attractive but remains a great challenge. Herein, ultrasmall NaGdF4@PLL nanodots (NDs) were developed as a novel class of MR contrast agent, which offers a high longitude relaxivity (6.42 mM(-1) s(-1)) for T1-weighted MRI and an excellent sensitive chemical exchange saturation transfer (CEST) effect for pH mapping (at +3.7 ppm). Further in vivo animal experiments show the feasibility of NaGdF4@PLL NDs as contrast agents for efficient kidney and brain tumor diagnosis and pH mapping, which will undoubtedly enhance the diagnosis accuracy and is beneficial for disease precaution and prognosis. Different from other complex dual-mode nanoprobes, the as-constructed NaGdF4@PLL NDs enable both anatomic and functional imaging on a single MR machine, which is a simple and cost-effective new approach to realize dual-mode MR imaging and holds great potential for future clinical application.

Combination therapy is a promising cancer treatment strategy that is usually based on the utilization of complicated nanostructures with multiple components functioning as photo-thermal energy transducers, photo-sensitizers, or dose intensifiers for photothermal therapy (PTT), photodynamic therapy (PDT), or radiation therapy (RT). In this study, ultrathin tungsten oxide nanowires (W18O49) were synthesized using a solvothermal approach and examined as a multifunctional theranostic nanoplatform. In vitro and in vivo analyses demonstrated that these nanowires could induce extensive heat- and singlet oxygen-mediated damage to cancer cells under 980 nm near infrared (NIR)-laser excitation. They were also shown to function as radiation dose intensifying agents that enhance irradiative energy deposition locally and selectively during radiation therapy. Compared to NIR-induced PTT/PDT and RT alone, W18O49-based synergistic tri-modal therapy eradicated xenograft tumors and no recurrence was observed within a 9-month follow up. Moreover, the strong X-ray attenuation ability of the tungsten element (Z = 74, 4.438 cm2·g–1, 100 KeV) qualified these nanowires as excellent contrast agents in X-ray-based imaging, such as diagnostic computed tomography (CT) and cone-beam CT for image-guided radiation therapy. Toxicity studies demonstrated minimal adverse effects on the hematologic system and major organs of mice within one month. In conclusion, these nanowires have shown significant potential for cancer therapy with inherent image guidance and synergistic effects from phototherapy and radiation therapy, which warrants further investigation.

Clinically applied chemotherapy and radiotherapy is sometimes not effective due to the limited dose acting on DNA chains resident in the nuclei of cancerous cells. Herein, we develop a new theranostic technique of "intranuclear radiosensitization" aimed at directly damaging the DNA within the nucleus by a remarkable synergetic chemo-/radiotherapeutic effect based on intranuclear chemodrug-sensitized radiation enhancement. To achieve this goal, a sub-50 nm nuclear-targeting rattle-structured upconversion core/mesoporous silica nanotheranostic system was firstly constructed to directly transport the radiosensitizing drug Mitomycin C (MMC) into the nucleus for substantially enhanced synergetic chemo-/radiotherapy and simultaneous magnetic/upconversion luminescent (MR/UCL) bimodal imaging, which can lead to efficient cancer treatment as well as multi-drug resistance circumvention in vitro and in vivo. We hope the technique of intranuclear radiosensitization along with the design of nuclear-targeting nanotheranostics will contribute greatly to the development of cancer theranostics as well as to the improvement of the overall therapeutic effectiveness.

Upconversion nanoparticles (UCNP), which utilize the sequential absorption and energy transfer steps to emit a higher energy photon after absorbing two or more low-energy excitation photons, have evoked great attention for bio-applications in areas such as biodetection and cancer imaging. This chapter focuses on the developments in the design and applications of hybrid UCNPs with emphasis on the fields of biodetection and cancer imaging. It summarizes the surface functionalization and discusses the strategies to sense biomolecules using the upconversion luminescence (UCL) signal of luminescence resonance energy transfer (LRET)- based UCNPs, such as LRET-on and LRET-off detection. The chapter discusses how to use hybrid UCNPs as an efficient nanoplatform to combine UCL imaging with other imaging modalities such as magnetic resonance imaging, computed tomography and radio-nuclear imaging for multimodality cancer imaging. Apart from the ligand engineering technique, coating processes like surface silanization and polymer self-assembly are other effective ways to obtain hydrophilic hybrid UCNPs.

Several decades of research have identified the specific tumor microenvironment (TME) to develop promising nanotheranostics, such as pH-sensitive imaging, acidity-sensitive starving therapy, and hydrogen peroxide-activated chemotherapy, etc. Herein, a novel TME-mediated nanoplatform employing antiferromagnetic pyrite nanocubes is presented, exploiting the intratumoral, overproduced peroxide for self-enhanced magnetic resonance imaging (MRI) and photothermal therapy (PTT)/chemodynamic therapy (CDT). Through the activation of excessive peroxide in the tumor microenvironment, pyrite can lead to in situ surface oxidation and generate hydroxyl radicals to kill tumor cells (i.e., CDT). The increase of the valence state of surface Fe significantly promotes the performance of MRI accompanied by CDT. Furthermore, the localized heat by photothermal treatment can accelerate the intratumoral Fenton process, enabling a synergetic PTT/CDT. To our best knowledge, this is the first study to use the TME-response valence-variable strategy based on pyrite for developing a synergetic nanotheranostic, which will open up a new dimension for the design of other TME-based anticancer strategies.

Insufficient or excess drug doses, due to unknown actual drug concentrations at the focus, are one of the main causes of chemotherapy failure for cancers. In this regard, the real-time monitoring of the release of anticancer drugs from nanoparticle drug delivery systems is of crucial importance, but it remains a critical and unsolved challenge. Herein, we report the proposal and development of a novel concept of real-time monitoring of NIR-triggered drug release in vitro and in vivo by using simultaneous upconverted luminescence (UCL) and magnetic resonance (MR) imaging. Such a monitoring strategy features the high sensitivity of UCL and the high-resolution, noninvasiveness, and tissue-depth-independence of MR imaging. The dual-mode real-time and quantitative monitoring of drug release can be applied to determine online the drug concentrations in vivo in the tissue regions of interest and, therefore, to avoid insufficient or excess drug dosings.

To integrate photothermal ablation (PTA) with radiotherapy (RT) for improved cancer therapy, we constructed a novel multifunctional core/satellite nanotheranostic (CSNT) by decorating ultrasmall CuS nanoparticles onto the surface of a silica-coated rare earth upconversion nanoparticle. These CSNTs could not only convert near-infrared light into heat for effective thermal ablation but also induce a highly localized radiation dose boost to trigger substantially enhanced radiation damage both in vitro and in vivo. With the synergistic interaction between PTA and the enhanced RT, the tumor could be eradicated without visible recurrence in 120 days. Notably, hematological analysis and histological examination unambiguously revealed their negligible toxicity to the mice within a month. Moreover, the novel CSNTs facilitate excellent upconversion luminescence/magnetic resonance/computer tomography trimodal imagings. This multifunctional nanocomposite is believed to be capable of playing a vital role in future oncotherapy by the synergistic effects between enhanced RT and PTA under the potential trimodal imaging guidance.

Cancer is one of the most common causes of death in the world, and chemotherapy remains to be one of the most frequent treatments for many cancers. However, its success has been greatly limited because of systemic toxicity due to the toxic effects by the nonspecific distribution of anti-cancer drugs. The drug delivery systems with the features of sustained drug release have attracted much attention owing to their enhanced therapeutic efficacy and reduced side effect. For example, mesoporous silica nanoparticles (MSNs) with interesting properties, such as thermal and photostability, tunable sizes, high loading capacity, and the ease of functionalization according to currently available results, have made the MSNs one of the most promising carriers for drug delivery. Although MSNs-based drug delivery systems have been proven effective, however, the use of cytotoxic drugs that are only released in the target area is much more preferred in clinical application. One way to prevent any premature release of anticancer drugs before they reach the target cells is to develop stimuli-responsive systems with controlled release features. Over the past decade, researches on MSNs-based light-controlled drug delivery systems have been carried out extensively because light as an external stimulus offers controllable drug release both spatially and temporally and thus exhibits great potentials for further biomedical applications. However, most of them have achieved limited success in applications in vitro and in vivo mainly because of the easy damages to both biological samples and living tissues by UV light used to excite the photosensitizer and extremely quick attenuation of UV light in tissues. To tackle this issue, it is highly desirable to develop NIR remote-controllable MSNs-based system which can be used both in vitro and in vivo, which, however, has not been well addressed and remains a great challenge. Compared to UV light, near-infrared (NIR) light is much less damaging to biological specimens and living tissues involved and has remarkably deeper tissue penetration. For example, Parak and co-workers reported that polyelectrolyte multilayer capsules loaded with cargo and plasmonic (Au or Ag) NPs can be used to release the cargo by NIR-photothermal heating. The cargo can be easily released with high efficiency under NIR exposure in one second. However, the size of these capsules can be as large as several microns, which will inevitably suffer from phagocytosis by reticuloendothelial systems (RES) when these systems are intravenously injected. Recently, upconverting nanoparticles (UCNPs) have emerged as an appealing candidate for the application of NIR light. Because of the unique ladder-like energy level structures of lanthanide ions (such as Tm, Er, and Ho), UCNPs are able to absorb NIR light and convert it into highenergy photons in a very broad range from the UV to the NIR region. Such a unique and fascinating photoluminescence property enables UCNPs to function as a NIR-induced mediator by coating caged compounds on the nanoparticle surface, and as a NIR-controlled photoswitch for reversible ring-closing and ring-opening transformation of a dithienylethene compound. Very recently, Branda and co-workers successfully used the NIR laser to dissociate block copolymer micelles by encapsulating UCNPs inside micelles. Since the copolymer micelles will inevitably suffer from self-degradation in biological environment, a combination between UCNPs and micelles may find few opportunities in practical bio-applications for remote-controlled drug delivery using a NIR laser in vitro and in vivo. In more recent studies, our group successfully demonstrated UCNP/methylene bluebased photodynamic therapy (PDT) through controlled singlet oxygen release triggered by NIR light. However, in spite of all the above efforts, reports on the direct NIRlight-controlled anticancer drug release for cancer therapy from a UCNPs-containing structure has not been found in the literature to date, which remains a great challenge in lightcontrolled drug delivery studies. Herein, we report a novel and general strategy for NIR light-triggered anticancer drug release based on amesoporous silica-coated UCNPs structure, designated as UCNP@mSiO2. Figure 1a shows the synthetic procedure for UCNP@mSiO2. The strategy consists of preparing NaYF4: TmYb@NaYF4 core–shell nanoparticles and subsequently coating the Tmdoped core–shell UCNPs with mesoporous silica. After [*] J. N. Liu, Prof. W. B. Bu, L. M. Pan, Prof. J. L. Shi State Key Laboratory of High Performance Ceramics and Superfine Microstructure Shanghai Institute of Ceramics, Chinese Academy of Sciences 1295 Ding-Xi Road, Shanghai 200050 (China) E-mail: wbbu@mail.sic.ac.cn jlshi@sunm.shcnc.ac.cn

Photothermal conversion is one of the most important keys in the fields of solar collection, photo-hyperthermia, etc., and its performance is highly dependent on the photothermal conversion materials used. Especially in cancer photo-hyperthermia, the presently available small-molecule- or nanomaterial-based agents still suffer from numerous drawbacks, such as nonspecific accumulation and inevitable side effects on normal tissues. Here we identify a Mo-based polyoxometalate cluster that can change its dimension from small (1 nm) to big (tens of nanometer), favoring its intratumoral accumulation, and enhance photothermal conversion in response to the intratumoral acidity and reducibility, demonstrating a previously unrealized tumor-specific photo-hyperthermia. Distinct from the well-researched nano-based agents, a unique electronic structure of this cluster has been identified as the origin of the observed acidity-induced self-assembly and reduction-promoted NIR absorbance. In addition to providing a promising clinical agent, this finding is expected to establish a new physicochemical paradigm for photothermal materials design based on clusters.

Following the "detect-to-treat" strategy, by biological engineering, the emerging upconversion nanoparticles (UCNPs) have become one of the most promising inorganic nanomedicines, and their biomedical applications have gradually shifted from multimodal tumor imaging to highly efficient cancer therapy. The past few years have witnessed a three-stage development of UCNP-based nanomedicines. On one hand, UCNPs can optimize each clinical treatment tool (chemotherapy, photodynamic therapy (PDT), radiotherapy (RT)) by controlled drug delivery/release, near-infrared (NIR)-excited deep PDT, and radiosensitization, respectively, all of which contribute greatly to the optimized treatment efficacy along with minimized side effects. On the other hand, several individual treatments can be "smartly" integrated into a single UCNP-based nanotheranostic system for multimodal synergetic therapy, which can further improve the overall therapeutic effectiveness. Especially, UCNPs provide more-effective strategies for overcoming tumor hypoxia, thus leading to an ideal treatment efficacy for complete eradication of solid tumors. Finally, the critical issues regarding the future development of UCNPs are discussed to promote the clinic-translational applications of UCNP-based nanomedicines, as well as realization of our "one drug fits all" dream.

Cancer therapy relying on a single therapeutic strategy generally remains suboptimal because each therapeutic approach has its own advantages and limitations. There is almost no doubt that future cancer therapies are very likely to rely on combinations of different treatment approaches, which may include surgery, chemotherapy, radiotherapy, PDT, and photothermal therapy (PTT). In this review, we discuss the most significant progress made in the past 5 years in the field of near infrared (NIR)-responsive nanotheranostics for synergetic cancer therapy. The nanoplatforms discussed include mesoporous silica nanoparticles, upconversion nanoparticles, Au-related nanomaterials, Fe3O4-related systems, and carbon-related materials.

To address the intractable issues such as the low performance or biocompatibility frequently encountered in previous CT, magnetic resonance (MR) and fluorescence trimodal imaging nanoprobes, a nanocomposite has been constructed by decorating gadolinium ions doped upconversion nanoparticle (Gd-doped UCNP) with radiopaque but fluorescence-transparent tantalum oxide (TaO(x), x ≈ 1). The as-synthesized water-soluble nanoparticle showed a litchi-like shape with an average size of ~30 nm and demonstrated extraordinarily high longitudinal and transverse relaxivity values (r(1) = 11.45 mM(-1)s(-1) and r(2) = 147.3 mM(-1)s(-1)) compared with the reported Gd-doped UCNPs to date. Obvious CT contrast enhancement was obtained by the combined effect between the radiopaque TaO(x) shell and the Gd-doped UCNP inner core. Strong upconversion luminescence (UCL) signal could unobstructedly penetrate out in virtue of high transparency of the TaO(x) shell. No mutual interference among different modalities of the upconversion nanolitchi (UCNL) was found, which ensured that the individual merits of every imaging modality could be brought into full play, demonstrated by in vitro and in vivo imagings. Furthermore, UCNLs showed only a slight effect on macrophages and RBCs in vitro and tissue in vivo.

Paramagnetic gadolinium (Gd-III)-ion-doped upconversion nanoparticles (UCNPs) are attractive optical-magnetic molecule imaging probes and are a highly promising nanoplatform for future theranostic nanomedicine design. However, the related relaxivity mechanism of this contrast agent is still not well understood and no significant breakthrough in relaxivity enhancement has been achieved. Here, the origin and optimization of both the longitudinal (r1) and transverse (r2) relaxivities are investigated using models of water soluble core@shell structured Gd3+-doped UCNPs. The longitudinal relaxivity enhancement of the nanoprobe is demonstrated to be co-contributed by inner-and outer-sphere mechanisms for ligand-free probes, and mainly by outer-sphere mechanism for silica-shielded probes. The origin of the transverse relaxivity is inferred to be mainly from an outer-sphere mechanism regardless of surface-coating, but with the r2 values highly related to the surface-state. Key factors that influence the observed relaxivities and r2/r1 ratios are investigated in detail and found to be dependent on the thickness of the NaGdF4 interlayer and the related surface modifications. A two orders of magnitude (105-fold) enhancement in r1 relaxivity and 18-fold smaller r2/r1 ratio compared to the first reported values are achieved, providing a new perspective for magnetic resonance (MR) sensitivity optimization and multimodality biological imaging using Gd3+-doped UCNPs.

Here we report the design and controlled synthesis of monodisperse and precisely size-controllable UCNP@mSiO(2) nanocomposites smaller than 50 nm by directly coating a mesoporous silica shell (mSiO(2)) on upconversion nanocrystals NaYF(4):Tm/Yb/Gd (UCNPs), which can be used as near-infrared fluorescence and magnetic resonance imaging (MRI) agents and a platform for drug delivery as well. Some key steps such as transferring hydrophobic UCNPs to the water phase by using cetyltrimethylammonium bromide (CTAB), removal of the excess amount of CTAB, and temperature-controlled ultrasonication treatment should be adopted and carefully monitored to obtain uniform upconversion core/mesoporous silica shell nanocomposites. The excellent performance of the core-shell-structured nanocomposite in near-infrared fluorescence and magnetic resonance imaging was also demonstrated.

As one of the most important branches of nanotechnology, nanotheranostic medicine that aims at integrating diagnostic/therapeutic functions in one system is expected to provide novel strategies for accurate imaging-guided therapy of human major diseases like cancer. Among various inorganic or organic theranostic probes, lanthanide-doped upconversion nanoparticles (UCNPs) demonstrate superior advantages in upconversion luminescent imaging by contrast with traditional luminescent probes as well as great potential in the development as multimodal imaging (e.g., magnetic resonance imaging, computed tomography imaging, etc.) probes by the selective doping of various functional ions (e.g., Gd3+, Yb3+, Ho3+, etc.). Furthermore, by suitable surface engineering (e.g., mesoporous silica coating, biological molecule conjugation etc.), UCNPs can simultaneously serve as delivery vehicles of drugs/photosensitizers for multimodal therapeutic applications (e.g., chemotherapy, photodynamic therapy, etc.) under the above significant multimodal imaging guidance. Herein, we summarize and discuss the very recent progresses in the engineering of UCNPs for multimodal imaging-guided therapeutic applications.

A novel in situ decomposition/reduction approach is developed to manufacture hollow core, magnetic, and mesoporous double-shell nanostructures (HMMNSs) via in situ decomposition and reduction of a β -FeOOH nanorod core and organosilicate-incorporated silica-shell precursor. The formed HMMNSs are then aminated by silanization for further covalent conjugation to rhodamine B isothiocyanate (RBITC) and poly(ethylene glycol) (PEG) chains. The resultant RBITC-grafted and PEGylated nanocomposites (HMMNS–R/Ps) have excellent blood compatibility and very low cytotoxicity towards HeLa and MCF-7 cells, and can be taken up by cancer cells effectively in a dose-dependent manner, as confi rmed by in vitro fl ow cytometry, confocal luminescence imaging, and magnetic resonance imaging (MRI) studies. In vivo MRI studies coupled with Prussian blue staining of slides from different organs show that the nanocomposites preferentially accumulate in liver and spleen after intravenous injection, which suggests a potential application of the nanocomposites as MRI contrast agents. Importantly, the HMMNS–R/P nanocomposites show high loading capacity for water-insoluble anticancer drugs (docetaxel or camptothecin) owing to the presence of a large inner cavity and enhanced surface area and pore volume. Furthermore, the drugloaded nanocomposites exhibit greater cytotoxicity than the corresponding free drugs. These results confi rm that the HMMNS–R/P nanocomposites are promising candidates for simultaneous bioimaging and drug delivery.

Oleic acid stabilized superparamagnetic iron oxide nanoparticles (SPION) were selected as the cores for fabrication of sub-50-nm monodisperse single-loaded SPION@SiO2 core–shell nanostructures. Parameters that influence the formation of SPION@SiO2 in the water-in-oil reverse microemulsion system have been systematically investigated. The sufficiently high concentration of well-dispersed SPION, together with an appropriately low injection rate of tetraethoxysilane, were found to be the keys to efficiently prevent the homogeneous nucleation of silica and obtain a high-quality single-loaded core–shell nanocomposite. A more detailed mechanism for incorporating oleic acid capped inorganic functional nanoparticles into silica is proposed on the basis of previous reports and our new experimental results. Finally, the as-synthesized SPION@SiO2 nanospheres are exploited as an MRI-enhanced contrast agent, and their contrast effect in solution is tested by using a clinical MRI instrument.

High efficiency green-luminescent LaPO 4 :Ce,Tb hierarchical nanostructures with uniform spindle shape have been successfully constructed by a simple Pluronic P123-assisted hydrothermal approach via self-assembling from single-crystalline nanowires. Their morphologies and structures were examined by scanning and transmission electron microscopy. The resulting uniform spindle-shaped microstructures are composed of several tens of aligned single-crystalline nanowires. The surfactant Pluronic P123 was found to play a crucial role in achieving uniform morphology of the final product as compared with the same material but synthesized without the surfactant Pluronic P123. These LaPO 4 :Ce,Tb spindle-shaped microstructures show efficient photoluminescence which is associated with its surface smoothness, high crystallization and uniform morphologies of the micro-architectures.

Monodisperse La2(MoO4)3:Yb,Tm microarchitectures with uniform waxberry-like morphology have been successfully constructed in large scale by a facile surfactant-assisted hydrothermal route, in which sodium lauryl sulfate (SLS) was used as the structure directing agent. It was found that the pH value was a crucial factor controlling the phase composition and purity, which was unaffected by surfactant SLS. The growth process of these waxberry-shaped microarchitectures has been examined in detail, and it was proved that a special dissolution−recrystallization transformation mechanism as well as a preferential adsorption of SLS process was responsible for the morphology evolution of the La2(MoO4)3:Yb,Tm microarchitectures. A mechanism for the formation of the waxberry-shape La2(MoO4)3:Yb,Tm microarchitectures was put forward. The specially shaped architectures showed blue up-conversion emission properties.

A new synthetic approach using the Pluronic P123-assisted hydrothermal reaction of lanthanum phosphate and europium-doped lanthanum phosphate has been developed, which results in the formation of uniform spindle-shaped microarchitectures most probably by a self-assembly process. Our results reveal that the obtained spindle-shaped microarchitectures consist of several tens of aligned single-crystalline nanowires with smooth, well-defined facets and highly uniform morphologies. These well-defined spindle-shaped microarchitectures show greatly enhanced photoluminescence in these compounds when compared to their counterparts of disordered arrangements. A possible formation mechanism for these spindle-shaped microarchitectures is presented and discussed.

Uniform three-dimensional La2(MoO4)3 nanostructures with a pompon shape have been successfully constructed by a simple surfactant-free hydrothermal approach via self-assembly from single-crystalline nanoflakes. The formation of the uniform pompon-shaped La2(MoO4)3 microarchitectures is closely related to the presence of a proper amount of ammonium ions, and it is proposed that the pompon-shaped microarchitecture forms through an electrostatic attraction/repulsion effect between the oppositely charged flat surface and the edge of nanoflakes. Without the introduction of ammonium ions, no pompon-shaped microarchitectures can be formed, and while under the presence of excess ammonium ions, the nanoflakes on the micropompons become amorphous, twisted, and rugged. The novel microarchitectures of the product can be successfully modified from spherical to columelliform by using a mixed solvent of water/ethanol. This simple and efficient method may provide a practical reference to the controlled synthesis of other microarchitectures.

Three-dimensional flowerlike europium-doped lanthanide molybdate [La2(MoO4)3:Eu] microarchitectures that exhibit efficient photoluminescence have been successfully synthesized via a facile hydrothe...

Biophotonic technology that uses light and ionizing radiation for positioned cancer therapy is a holy grail in the field of biomedicine because it can overcome the systemic toxicity and adverse side effects of conventional chemotherapy. However, the existing biophotonic techniques fail to achieve the satisfactory treatment efficacy, which remains a big challenge for clinical implementation. Herein, we develop a novel theranostic technique of "intranuclear biophotonics" by the smart design of a nuclear-targeting biophotonic system based on photo-/radio-sensitizers covalently co-loaded upconversion nanoparticles. These nuclear-targeting biophotonic agents can not only generate a great deal of multiple cytotoxic reactive oxygen species in the nucleus by making full use of NIR/X-ray irradiation, but also produce greatly enhanced intranuclear synergetic radio-/photodynamic therapeutic effects under the magnetic/luminescent bimodal imaging guidance, which may achieve the optimal efficacy in treating radio-resistant tumors. We anticipate that the highly effective intranuclear biophotonics will contribute significantly to the development of biophotonic techniques and open new perspectives for a variety of cancer theranostic applications.

Next generation theranostic devices will rely on the smart integration of different functional moieties into one system. These individual chemical elements will have a variety of desired chemical and physical properties and will need to behave in a multifunctional manner. Researchers have used upconversion nanoparticles (UCNPs) as a basis for superior imaging probes to locate cancerous lesions. The features of these nanoparticles, such as large anti-Stokes shifts, sharp emission bands, long-lived luminescence, and high resistance to photobleaching, have produced versatile probes. One way to improve these probes is to add a layer of dense or mesoporous silica to the outer surface of UCNPs (UCNP@SiO2). These modified UCNPs are chemically stable and much less cytotoxic than the original UCNPs. In addition, their surface can be easily modified to introduce various functional groups (e.g., -NH2, -COOH, -SH) via silanization, which facilitates conjugations with various biological molecules for multimodal imaging or synergetic therapeutics. This versatility makes UCNP@SiO2 particles excellent platforms for the construction of efficient theranostics. In this Account, we provide a comprehensive summary of recent progress in the development of UCNP@SiO2 nanocomposites for theranostics in the hope of speeding their translation into the clinic. We first discuss the major design principles and protocols for engineering various nanocomposites based on UCNP@SiO2 structures including those coated with dense silica, mesoporous silica, or hollow mesoporous silica. Next we summarize several representative efforts that probe the relaxivity mechanisms of these nanostructures as a way to optimize magnetic resonance sensitivity, multimode cancer imaging, near-infrared light-triggered chemotherapy, photodynamic therapy, and synergetic therapy (the combination of radiotherapy with chemotherapy, thermotherapy, or photodynamic therapy) using UCNP@SiO2-based theranostics. By rational integration of a wide range of features that convey multiple functions (such as imaging and therapy) into the structure or onto the surfaces of UCNP@SiO2, the constructed theranostics show promise for multimodal cancer imaging, biosensing, and effective cancer therapy. Finally, we discuss the limitations of UCNP@SiO2 nanostructures, the difficulties in the design of smart theranostics, and their potential role in clinical cancer research.

Hypoxia is a distinct feature of malignant solid tumors, which is a possible causative factor for the serious resistance to chemo- and radiotherapy or the development of invasion and metastasis. The exploration of nanosensors with the capabilities like the accurate diagnosis of hypoxic level will be helpful to estimate the malignant degree of tumor and subsequently implement more effective personalized treatment. Here, we report the design and synthesis of nanosensors that can selectively and reversibly detect the level of hypoxia both in vitro and in vivo. The designed nanosensor is composed of two main moieties: oxygen indicator [Ru(dpp)3](2+)Cl2 for detection of hypoxia and upconversion nanoparticles for offering the excitation light of [Ru(dpp)3](2+)Cl2 by upconversion process under 980 nm exposure. The results show that the nanosensors can reversibly become quenched or luminescent under hyperoxic or hypoxic conditions, respectively. Compared with free [Ru(dpp)3](2+)Cl2, the designed nanosensors exhibit enhanced sensitivity for the detection of oxygen in hypoxic regions. More attractively, the nanosensors can image hypoxic regions with high penetration depth because the absorption and emission wavelength are within the NIR and far-red region, respectively. Most importantly, nanosensors display a high selectivity for detection of relevant oxygen changes in cells and zebrafish.

Upconversion nanoparticle (UCNP) has been attracting growing interests in the last few years owing to their unique upconversion luminescence features. Although the size and morphology control of UCNP have been well-documented, engineering of ultrasmall-sized UCNP with excellent optical properties is still in its early stage. With increasing interests in using UCNP as deeper tissue imaging probe, some new strategies have been developed for enhancing the emission efficiency of red and near-infrared bands. Also, doping suitable ions into UCNP crystal lattices has been accepted as one of the most unique and efficient techniques for integrating nearly all clinical relevant imaging modalities together in one single UCNP. Cancer multimodal imaging (or therapy) with these lanthanide ions-doped UCNPs has become a new hot topic in this field. Here, we summarized the very recent advances in engineering of UCNP for biological imaging and therapy.

The design, application, and translation of targeted multimodality molecular imaging probes based on nanotechnology have attracted increasing attentions during the last decade and will continue to play vital roles in cancer diagnosis and personalized medicine. With the growing awareness of drawbacks of traditional organic dyes and quantum dots, biocompatible lanthanide ion doped upconversion nanoparticles have emerged as promising candidates for clinically translatable imaging probes, owing to their unique features that are suitable for future targeted multimodal imaging in living subjects. In this review, we summarized the recent advances in the field of functionalized upconversion nanoparticles (f-UCNP) for biological imaging and therapy in vivo, and discussed the future research directions, obstacles ahead, and the potential use of f-UCNP in translational research.

A new generation of photothermal theranostic agents is developed based on PEGylated WS2 nanosheets. Bimodal in vivo CT/photoacoustic imaging reveals strong tumor contrast after either intratumoral or intravenous injection of WS2 -PEG. In vivo photothermal treatment is then conducted in a mouse tumor model, achieving excellent therapeutic efficacy with complete ablation of tumors. This work promises further exploration of transition-metal dichalcogenides for biomedical applications, such as cancer imaging and therapy.

Most hypoxic tumors are insensitive to radiation, which is a major obstacle in the development of conventional radiotherapy for tumor treatment. Some drugs, such as cisplatin (CDDP), have been extensively used both as an anticancer drug and clinically as a radiosensitizer to enhance radiotherapy. Herein, we develop rattle-structured multifunctional up-conversion core/porous silica shell nanotheranostics (UCSNs) for delivering CDDP to tumors for synergetic chemo-/radiotherapy by CDDP radiosensitization and magnetic/luminescent dual-mode imaging. UCSNs had a dynamic light scattering diameter of 79.1 nm and excellent water dispersity and stability. In vitro studies showed that CDDP loaded in UCSNs (UCSNs-CDDP) was more effective than free CDDP as a radiosensitizer. After injection, UCSNs-CDDP also demonstrated unambiguously enhanced radiotherapy efficacy in vivo. Our report aims at presenting a novel strategy in biomedical nanotechnology that allows simultaneous dual-mode imaging and localized therapy via synergetic chemo-/radiotherapy, which may achieve optimized therapeutic efficacy in cancer treatment.

Hybridization produces the better: Colloidal hollow periodic mesoporous organosilica nanoparticles (HPMO NPs) with tunable compositions and highly hybridized nanostructures are successfully synthesized by a simple, easily scale-up but versatile silica-etching chemistry (alkaline or HF etching) for their applications in nano-fabrication and nano-medicine.

Nuclear-targeted therapy by delivering anticancer drug directly into cancer cell nuclei can elicit synergistic therapeutic effects and kill these cancer cells with much enhanced efficiencies. Besides nuclear targeting, another difficulty in nuclear-targeted therapy is how to achieve real-time monitoring of the therapy process simultaneously. In this article we report on the development of multifunctional upconversion nanoparticles (UCNPs) which were able to target cancer cell nuclei, and thus deliver the anticancer drug directly to the nuclear region and simultaneously image cell nucleus by magnetic resonance (MR)/upconversion fluorescent for real-time guidance of their therapeutic action simultaneously. The Er/Yb-doped NaYF(4) core and NaGdF(4) shell endow the core/shell structured UCNPs with enhanced upconversion fluorescent imaging and more sensitive T(1)-MR imaging performances, and the surface conjugation of TAT peptide served as a key role in the nuclear targeting and nuclear transport process. This multifunctional UCNPs-based nano-theranostic was used to improve the efficacy of DOX in Hela humor tumor models, by direct DOX delivery to the nucleus under the synchronous monitoring of the nano-theranostics. Further development of this technology may provide more exciting opportunities in treating cancer disease by nuclear-targeted therapy.

Upconverting nanoparticles (UCNPs) with fascinating properties hold great potential as nanotransducers for solving the problems that traditional photodynamic therapy (PDT) has been facing. In this report, by using well-selected bifunctional gadolinium (Gd)-ion-doped UCNPs and water-soluble methylene blue (MB) combined with the water-in-oil reverse microemulsion technique, we have succeeded in developing a new kind of UCNP/MB-based PDT drug, NaYF(4):Er/Yb/Gd@SiO(2)(MB), with a particle diameter less than 50 nm. Great efforts have been made to investigate the drug-formation mechanism and provide detailed physical and photochemical characterizations and the potential structure optimization of the as-designed PDT drug. We envision that such a PDT drug will become a potential theranostic nanomedicine for future near-infrared laser-triggered photodynamic therapy and simultaneous magnetic/optical bimodal imaging.

We report the direct fabrication of mesoporous zeolite with a hollow spherical/ellipsoidal capsule structure by using conventional TPAOH and CTAB as soft micro- and mesopore generating templates; the mesoporous zeolite shows a high surface area of 717 m(2) g(-1) and small mesopore size of around 3 nm.

Uniform CePO(4)@LaPO(4) and CePO(4):Tb(3+)@LaPO(4) one-dimensional single-crystalline nanocable heterostructures with highly enhanced photoluminescent emission have been synthesized via a mild and simple hydrothermal approach. The resulting one-dimensional single-crystalline nanocable heterostructures have smooth and uniform LaPO(4) sheaths, which is of great significance in effectively eliminating surface trap-states and suppressing the energy quenching in energy-transfer processes. The photoluminescence results for these one-dimensional nanocable heterostructures illustrate that the uniform LaPO(4) sheaths remarkably increase the luminescent efficiency.