Aptamer‐Directed Synthesis of Multifunctional Lanthanide‐Doped Porous Nanoprobes for Targeted Imaging and Drug Delivery

Multifunctional lanthanide‐doped porous nanoparticles are prepared via a facile one‐step solvothermal route by employing aptamers as the biotemplate. The nanoparticles feature excellent aqueous dispersibility and biospecific properties and could work as effective nanoprobes for targeted imaging and drug delivery. With aptamer being in principle available for any kind of target, this synthetic strategy may open the door to a new generation of nanoprobes for bioapplications such as time‐resolved biodetection, multimode bioimaging/biolabeling, and targeted cancer therapy.     

High‐Performance Upconversion Nanoprobes for Multimodal MR Imaging of Acute Ischemic Stroke

Multimodal magnetic resonance (MR) imaging, including MR angiography (MRA) and MR perfusion (MRP), plays a critical role in the diagnosis and surveillance of acute ischemic stroke. However, these techniques are hindered by the low T₁ relaxivity, short circulation time, and high leakage rate from vessels of clinical Magnevist. To address these problems, nontoxic polyethylene glycol (PEG)ylated upconversion nanoprobes (PEG‐UCNPs) are synthesized and first adopted for excellent MRA and MRP imaging, featuring high diagnostic sensitivity toward acute ischemic stroke in high‐resolution imaging. The investigations show that the agent possesses superior advantages over clinical Magnevist, such as much higher relaxivity, longer circulation time, and lower leakage rate, which guarantee much better imaging efficiency. Remarkably, an extremely small dosage (5 mg Gd kg^?1) of PEG‐UCNPs provides high‐resolution MRA imaging with the vascular system delineated much clearer than the Magnevist with clinical dosage as high as 108 mg Gd kg^?1. On the other hand, the long circulation time of PEG‐UCNPs enables the surveillance of the progression of ischemic stroke using MRA or MRP. Once translated, these PEG‐UCNPs are expected to be a promising candidate for substituting the clinical Magnevist in MRA and MRP, which will significantly lengthen the imaging time window and improve the overall diagnostic efficiency.     

J‐Aggregates of Organic Dye Molecules Complexed with Iron Oxide Nanoparticles for Imaging‐Guided Photothermal Therapy Under 915‐nm Light

Recently, the development of nano‐theranostic agents aiming at imaging guided therapy has received great attention. In this work, a near‐infrared (NIR) heptamethine indocyanine dye, IR825, in the presence of cationic polymer, polyallylamine hydrochloride (PAH), forms J‐aggregates with red‐shifted and significantly enhanced absorbance. After further complexing with ultra‐small iron oxide nanoparticles (IONPs) and the followed functionalization with polyethylene glycol (PEG), the obtained IR825@PAH‐IONP‐PEG composite nanoparticles are highly stable in different physiological media. With a sharp absorbance peak, IR825@PAH‐IONP‐PEG can serve as an effective photothermal agent under laser irradiation at 915 nm, which appears to be optimal in photothermal therapy application considering its improved tissue penetration compared with 808‐nm light and much lower water heating in comparison to 980‐nm light. As revealed by magnetic resonance (MR) imaging, those nanoparticles after intravenous injection exhibit high tumor accumulation, which is then harnessed for in vivo photothermal ablation of tumors, achieving excellent therapeutic efficacy in a mouse tumor model. This study demonstrates for the first time that J‐aggregates of organic dye molecules are an interesting class of photothermal material, which when combined with other imageable nanoprobes could serve as a theranostic agent for imaging‐guided photothermal therapy of cancer.     

915 nm Light‐Triggered Photodynamic Therapy and MR/CT Dual‐Modal Imaging of Tumor Based on the Nonstoichiometric Na0.52YbF3.52:Er Upconversion Nanoprobes

Lanthanide (Ln³⁺)‐doped upconversion nanoparticles (UCNPs) as a new generation of multimodal bioprobes have attracted great interest for theranostic purpose. Herein, red emitting nonstoichiometric Na_0.52YbF_3.52:Er UCNPs of high luminescence intensity and color purity are synthesized via a facile solvothermal method. The red UC emission from the present nanophosphors is three times more intense than the well‐known green emission from the ≈30 nm sized hexagonal‐phase NaYF₄:Yb,Er UCNPs. By utilizing Na_0.52YbF_3.52:Er@SrF₂ UCNPs as multifunctional nanoplatforms, highly efficient in vitro and in vivo 915 nm light‐triggered photodynamic therapies are realized for the first time, with dramatically diminished overheating yet similar therapeutic effects in comparison to those triggered by 980 nm light. Moreover, by virtue of the high transverse relaxivity (r ₂) and the strong X‐ray attenuation ability of Yb³⁺ ions, these UCNPs also demonstrate good performances as contrast agents for high contrast magnetic resonance and X‐ray computed tomography dual‐modal imaging. Our research shows the great potential of the red emitting Na_0.52YbF_3.52:Er UCNPs for multimodal imaging‐guided photodynamic therapy of tumors.     

Lighting Up MicroRNA in Living Cells by the Disassembly of Lock‐Like DNA‐Programmed UCNPs‐AuNPs through the Target Cycling Amplification Strategy

Intracellular microRNAs imaging based on upconversion nanoprobes has great potential in cancer diagnostics and treatments. However, the relatively low detection sensitivity limits their application. Herein, a lock‐like DNA (LLD) generated by a hairpin DNA (H1) hybridizing with a bolt DNA (bDNA) sequence is designed, which is used to program upconversion nanoparticles (UCNPs, NaYF₄@NaYF₄:Yb, Er@NaYF₄) and gold nanoparticles (AuNPs). The upconversion emission is quenched through luminescence resonance energy transfer (LRET). The multiple LLD can be repeatedly opened by one copy of target microRNA under the aid of fuel hairpin DNA strands (H2) to trigger disassembly of AuNPs from the UCNP, resulting in the lighting up of UCNPs with a high detection signal gain. This strategy is verified using microRNA‐21 as model. The expression level of microRNA‐21 in various cells lines can be sensitively measured in vitro, meanwhile cancer cells and normal cells can be easily and accurately distinguished by intracellular microRNA‐21 imaging via the nanoprobes. The detection limit is about 1000 times lower than that of the previously reported upconversion nanoprobes without signal amplification. This is the first time a nonenzymatic signal amplification method has been combined with UCNPs for imaging intracellular microRNAs, which has great potential for cancer diagnosis.     

Glutathione Mediated Size‐Tunable UCNPs‐Pt(IV)‐ZnFe2O4 Nanocomposite for Multiple Bioimaging Guided Synergetic Therapy

Here a multifunctional nanoplatform (upconversion nanoparticles (UCNPs)‐platinum(IV) (Pt(IV))?ZnFe₂O₄, denoted as UCPZ) is designed for collaborative cancer treatment, including photodynamic therapy (PDT), chemotherapy, and Fenton reaction. In the system, the UCNPs triggered by near‐infrared light can convert low energy photons to high energy ones, which act as the UV–vis source to simultaneously mediate the PDT effect and Fenton's reaction of ZnFe₂O₄ nanoparticles. Meanwhile, the Pt(IV) prodrugs can be reduced to high virulent Pt(II) by glutathione in the cancer cells, which can bond to DNA and inhibit the copy of DNA. The synergistic therapeutic effect is verified in vitro and in vivo results. The cleavage of Pt(IV) from UCNPs during the reduction process can shift the larger UCPZ nanoparticles (NPs) to the smaller ones, which promotes the enhanced permeability and retention (EPR) and deep tumor penetration. In addition, due to the inherent upconversion luminescence (UCL) and the doped Yb³⁺ and Fe³⁺ in UCPZ, this system can serve as a multimodality bioimaging contrast agent, covering UCL, X‐ray computed tomography, magnetic resonance imaging, and photoacoustic. A smart all‐in‐one imaging‐guided diagnosis and treatment system is realized, which should have a potential value in the treatment of tumor.     

Control of the in vivo Biodistribution of Hybrid Nanoparticles with Different Poly(ethylene glycol) Coatings

Fluorescent nanoparticles containing a gadolinium oxide core are very attractive because they are able to combine both imaging (fluorescence imaging, magnetic resonance imaging) and therapy (X‐ray therapy and neutron‐capture therapy) techniques. The exploitation of these multifunctional particles for in vivo applications requires accurate control of their biodistribution. The postfunctionalization of these particles by four different poly(ethylene glycol) derivatives, which differ by chain length and end group, exerts a great influence on the ζ potential of the nanoparticles and on their biodistribution after intravenous injection to HEK‐β3‐tumor‐bearing mice. This study reveals that the behavior of PEGylated nanoparticles, which was monitored by in vivo fluorescence imaging, depends on both the chain length and the end group of the PEG chain.     

Synthesis,self-assembly,and characterization of PEG-coated iron oxide nanoparticles as potential MRI contrast agent

Aim: Investigated the self-assembly and characterization of novel antifouling polyethylene glycol (PEG)-coated iron oxide nanoparticles as nanoprobes for magnetic resonance imaging (MRI) contrast agent. Method: Monodisperse oleic acid-coated superparamagnetic iron oxide cores are synthesized by thermal decomposition of iron oleate. The self-assembly behavior between iron oxide cores and PEG-lipid conjugates in water and their characteristics are confirmed by transmission electron microscope, X-ray diffraction, thermogravimetric analysis, Fourier transform infrared spectroscopy, and vibrating sample magnetometer. Result: Dynamic light scattering shows superparamagnetic iron oxide nanoparticles coated with PEG are stable in water for pH of 3–10 and ionic strengths up to 0.3 M NaCl, and are protein resistant in physiological conditions. Additionally, in vitro MRI study demonstrates the efficient magnetic resonance imaging contrast characteristics of the iron oxide nanoparticles. Conclusion: The result indicates that the novel antifouling PEG-coated superparamagnetic iron oxide nanoparticles could potentially be used in a wide range of applications such as biotechnology, MRI, and magnetic fluid hyperthermia.     

Non‐Magnetic Injectable Implant for Magnetic Field‐Driven Thermochemotherapy and Dual Stimuli‐Responsive Drug Delivery: Transformable Liquid Metal Hybrid Platform for Cancer Theranostics

Transformable liquid metal (LM)‐based materials have attracted considerable research interest in biomedicine. However, the potential biomedical applications of LMs have not yet been fully explored. Herein, for the first trial, the inductive heating property of gallium–indium eutectic alloy (EGaIn) under alterative magnetic field is systematically investigated. By virtue of its inherent metallic nature, LM possesses excellent magnetic heating property as compared to the conventional magnetite nanoparticles, therefore enabling its unique application as non‐magnetic agents in magnetic hyperthermia. Moreover, the extremely high surface tension of LM could be dramatically lowered by a rather facile PEGylation approach, making LM an ideal carrier for other theranostic cargos. By incorporating doxorubicin (DOX)‐loaded mesoporous silica (DOX‐MS) within PEGylated LM, a magnetic field‐driven transformable LM hybrid platform capable of pH/AFM dual stimuli‐responsive drug release and magnetic thermochemotherapy are successfully fabricated. The potential application for breast cancer treatment is demonstrated. Furthermore, the large X‐ray attenuation ability of LM endows the hybrid with the promising ability for CT imaging. This work explores a new biomedical use of LM and a promising cancer treatment protocol based on LM hybrid for magnetic hyperthermia combined with dual stimuli‐responsive chemotherapy and CT imaging.     

Manganese Dioxide Coated WS2@Fe3O4/sSiO2 Nanocomposites for pH‐Responsive MR Imaging and Oxygen‐Elevated Synergetic Therapy

Recently, the development of multifunctional theranostic nanoplatforms to realize tumor‐specific imaging and enhanced cancer therapy via responding or modulating the tumor microenvironment (TME) has attracted tremendous interests in the field of nanomedicine. Herein, tungsten disulfide (WS₂) nanoflakes with their surface adsorbed with iron oxide nanoparticles (IONPs) via self‐assembly are coated with silica and then subsequently with manganese dioxide (MnO₂), on to which polyethylene glycol (PEG) is attached. The obtained WS₂‐IO/S@MO‐PEG appears to be highly sensitive to pH, enabling tumor pH‐responsive magnetic resonance imaging with IONPs as the pH‐inert T2 contrast probe and MnO₂ as the pH‐sensitive T1 contrast probe. Meanwhile, synergistic combination tumor therapy is realized with such WS₂‐IO/S@MO‐PEG, by utilizing the strong near‐infrared light and X‐ray absorbance of WS₂ for photothermal therapy (PTT) and enhanced cancer radiotherapy (RT), respectively, as well as the ability of MnO₂ to decompose tumor endogenous H₂O₂ and relieve tumor hypoxia to further overcome hypoxia‐associated radiotherapy resistance. The combination of PTT and RT with WS₂‐IO/S@MO‐PEG results in a remarkable synergistic effect to destruct tumors. This work highlights the promise of developing multifunction nanocomposites for TME‐specific imaging and TME modulation, aiming at precision cancer synergistic treatment.     

Phytotoxicity,Translocation, and Biotransformation of NaYF4 Upconversion Nanoparticles in a Soybean Plant

The increasing uses of rare‐earth‐doped upconversion nanoparticles (UCNPs) have obviously caused many concerns about their potential toxicology on live organisms. In addition, the UCNPs can be released into the environment, then transported into edible crop plants, and finally entered into food chain. Here, the soybean is chosen as a model plant to study the subchronic phytotoxicity, translocation, and biotransformation of NaYF₄ UCNPs. The incubation with UCNPs at a relative low concentration of 10 μg mL^?1 leads to growth promotion for the roots and stems, while concentration exceeding 50 μg mL^?1 brings concentration‐dependent inhibition. Upconversion luminescence imaging and scanning electron microscope characterization show that the UCNPs can be absorbed by roots and parts of the adsorbed UCNPs are then transported through vessels to stems and leaves. The near‐edge X‐ray absorption fine structure spectra reveal that the adsorbed NaYF₄ nanoparticles are relatively stable during a 10 d incubation. Energy‐dispersive X‐ray spectrum further indicates that a small amount of NaYF₄ is dissolved/digested and can transform into Y‐phosphate clusters in roots.     

Drug‐Loaded Mesoporous Tantalum Oxide Nanoparticles for Enhanced Synergetic Chemoradiotherapy with Reduced Systemic Toxicity

Combining chemotherapy and radiotherapy (chemoradiotherapy) has been widely applied in many clinical practices, showing promises in enhancing therapeutic outcomes. Nontoxic nanocarriers that not only are able to deliver chemotherapeutics into tumors, but could also act as radiosensitizers to enhance radiotherapy would thus be of great interest in the development of chemoradiotherapies. To achieve this aim, herein mesoporous tantalum oxide (mTa₂O₅) nanoparticles with polyethylene glycol (PEG) modification are fabricated. Those mTa₂O₅‐PEG nanoparticles could serve as a drug delivery vehicle to allow efficient loading of chemotherapeutics such as doxorubicin (DOX), whose release appears to be pH responsive. Meanwhile, owing to the interaction of Ta with X‐ray, mTa₂O₅‐PEG nanoparticles could offer an intrinsic radiosensitization effect to increase X‐ray‐induced DNA damages during radiotherapy. As a result, DOX‐loaded mTa₂O₅‐PEG (mTa₂O₅‐PEG/DOX) nanoparticles can offer a strong synergistic therapeutic effect during the combined chemoradiotherapy. Furthermore, in chemoradiotherapy, such mTa₂O₅‐PEG/DOX shows remarkably reduced side effects compared to free DOX, which at the same dose appears to be lethal to animals. This work thus presents a new type of mesoporous nanocarrier particularly useful for the delivery of safe and effective chemoradiotherapy.     

Manganese‐Based Layered Double Hydroxide Nanoparticles as a T1‐MRI Contrast Agent with Ultrasensitive pH Response and High Relaxivity

Recently, Mn(II)‐containing nanoparticles have been explored widely as an attractive alternative to Gd(III)‐based T₁‐weighted magnetic resonance imaging (MRI) contrast agents (CAs) for cancer diagnosis. However, as far as it is known, no Mn‐based MRI CAs have been reported to sensitively respond to a very weakly acidic environment (pH 6.5–7.0, i.e., the pH range in a tumor microenvironment) with satisfactory imaging performance. Here, recently devised pH‐ultrasensitive Mn‐based layered double hydroxide (Mn‐LDH) nanoparticles with superb longitudinal relaxivity (9.48 mm ^?1 s^?1 at pH 5.0 and 6.82 mm ^?1 s^?1 at pH 7.0 vs 1.16 mm ^?1 s^?1 at pH 7.4) are reported, which may result from the unique microstructure of Mn ions in Mn‐LDH, as demonstrated by extended X‐ray absorption fine structure. Further in vivo imaging reveals that Mn‐LDH nanoparticles show clear MR imaging for tumor tissues in mice for 2 d post intravenous injection. Thus, this novel Mn‐doped LDH nanomaterial, together with already demonstrated capacity for drug and gene delivery, is a very potential theranostic agent for cancer diagnosis and treatment.     

NIR Biosensing of Neurotransmitters in Stem Cell‐Derived Neural Interface Using Advanced Core–Shell Upconversion Nanoparticles

Nondestructive neurotransmitter detection and real‐time monitoring of stem cell differentiation are both of great significance in the field of neurodegenerative disease and regenerative medicine. Although luminescent biosensing nanoprobes have been developed to address this need, they have intrinsic limitations such as autofluorescence, scattering, and phototoxicity. Upconversion nanoparticles (UCNPs) have gained increasing attention for various biomedical applications due to their high photostability, low auto‐fluorescent background, and deep tissue penetration; however, UCNPs also suffer from low emission intensities due to undesirable energy migration pathways. To address the aforementioned issue, a single‐crystal core–shell–shell “sandwich” structured UCNP is developed that is designed to minimize deleterious energy back‐transfer to yield bright visible emissions using low power density excitations. These UCNPs show a remarkable enhancement of luminescent output relative to conventional β‐NaYF4:Yb,Er codoped UCNPs and β‐NaYF4:Yb,Er@NaYF4:Yb “active shell” alike. Moreover, this advanced core–shell–shell UCNP is subsequently used to develop a highly sensitive biosensor for the ultrasensitive detection of dopamine released from stem cell‐derived dopaminergic‐neurons. Given the challenges of in situ detection of neurotransmitters, the developed NIR‐based biosensing of neurotransmitters in stem cell‐derived neural interfaces present a unique tool for investigating single‐cell mechanisms associated with dopamine, or other neurotransmitters, and their roles in neurological processes.     

Strategies for Constructing Upconversion Luminescence Nanoprobes to Improve Signal Contrast

Lanthanide‐doped upconversion nanoparticles (UCNPs) can convert two or more lower‐energy near‐infrared photons to a single photon with higher energy, which makes them particularly suitable for constructing nanoprobes with large imaging depth and minimal interference of autofluorescence and light scattering from biosamples. Furthermore, they feature excellent photostability, sharp and narrow emissions, and large anti‐Stokes shift, which confer them the capability of long‐period bioimaging and real‐time tracking. In recent years, UCNPs‐based nanoprobes (UC‐nanoprobes) have been attracting increasing interest in biological and medical research. Signal contrast, the ratio of signal intensity after and before the reaction of the probe and target, is the determinant factor of the sensitivity of all reaction‐based probes. This progress report presents the methods of constructing UC‐nanoprobes, with a focus fixed on recent strategies to improve the signal contrast, which have kept on promoting the bioapplication of this type of probe.     

Grafting Single Molecule Magnets on Gold Nanoparticles

The chemical synthesis and characterization of the first hybrid material composed by gold nanoparticles and single molecule magnets (SMMs) are described. Gold nanoparticles are functionalized via ligand exchange using a tetrairon(III) SMM containing two 1,2‐dithiolane end groups. The grafting is evidenced by the shift of the plasmon resonance peak recorded with a UV–vis spectrometer, by the suppression of nuclear magnetic resonance signals, by X‐ray photoemission spectroscopy peaks, and by transmission electron microscopy images. The latter evidence the formation of aggregates of nanoparticles as a consequence of the cross‐linking ability of Fe₄ through the two 1,2‐dithiolane rings located on opposite sides of the metal core. The presence of intact Fe₄ molecules is directly proven by synchrotron‐based X‐ray absorption spectroscopy and X‐ray magnetic circular dichroism spectroscopy, while a detailed magnetic characterization, obtained using electron paramagnetic resonance and alternating‐current susceptibility, confirms the persistence of SMM behavior in this new hybrid nanostructure.     

Shedding Light on Metal‐Based Nanoparticles in Zebrafish by Computed Tomography with Micrometer Resolution

Metal‐based nanoparticles are clinically used for diagnostic and therapeutic applications. After parenteral administration, they will distribute throughout different organs. Quantification of their distribution within tissues in the 3D space, however, remains a challenge owing to the small particle diameter. In this study, synchrotron radiation‐based hard X‐ray tomography (SRμCT) in absorption and phase contrast modes is evaluated for the localization of superparamagnetic iron oxide nanoparticles (SPIONs) in soft tissues based on their electron density and X‐ray attenuation. Biodistribution of SPIONs is studied using zebrafish embryos as a vertebrate screening model. This label‐free approach gives rise to an isotropic, 3D, direct space visualization of the entire 2.5 mm‐long animal with a spatial resolution of around 2 µm. High resolution image stacks are available on a dedicated internet page ( http://zebrafish.pharma-te.ch ). X‐ray tomography is combined with physico‐chemical characterization and cellular uptake studies to confirm the safety and effectiveness of protective SPION coatings. It is demonstrated that SRμCT provides unprecedented insights into the zebrafish embryo anatomy and tissue distribution of label‐free metal oxide nanoparticles.     

Responsive Upconversion Nanoprobe for Background‐Free Hypochlorous Acid Detection and Bioimaging

Responsive nanoprobes play an important role in bioassay and bioimaging, early diagnosis of diseases and treatment monitoring. Herein, a upconversional nanoparticle (UCNP)‐based nanoprobe, Ru@UCNPs, for specific sensing and imaging of hypochlorous acid (HOCl) is reported. This Ru@UCNP nanoprobe consists of two functional components,, i.e., NaYF₄:Yb, Tm UCNPs that can convert near infrared light‐to‐visible light as the energy donor, and a HOCl‐responsive ruthenium(II) complex [Ru(bpy)₂(DNCH‐bpy)](PF₆)₂ (Ru‐DNPH) as the energy acceptor and also the upconversion luminescence (UCL) quencher. Within this luminescence resonance energy transfer nanoprobe system, the UCL OFF–ON emission is triggered specifically by HOCl. This triggering reaction enables the detection of HOCl in aqueous solution and biological systems. As an example of applications, the Ru@UCNPs nanoprobe is loaded onto test papers for semiquantitative HOCl detection without any interference from the background fluorescence. The application of Ru@UCNPs for background‐free detection and visualization of HOCl in cells and mice is successfully demonstrated. This research has thus shown that Ru@UCNPs is a selective HOCl‐responsive nanoprobe, providing a new way to detect HOCl and a new strategy to develop novel nanoprobes for in situ detection of various biomarkers in cells and early disgnosis of animal diseases.     

Iodine‐Rich Semiconducting Polymer Nanoparticles for CT/Fluorescence Dual‐Modal Imaging‐Guided Enhanced Photodynamic Therapy

Photodynamic therapy (PDT) is a promising technique for cancer therapy, providing good therapeutic efficacy with minimized side effect. However, the lack of oxygen supply in the hypoxic tumor site obviously restricts the generation of singlet oxygen (¹O₂), thus limiting the efficacy of PDT. So far, the strategies to improve PDT efficacy usually rely on complicated nanosystems, which require sophisticated design or complex synthetic procedure. Herein, iodine‐rich semiconducting polymer nanoparticles (SPN‐I) for enhanced PDT, using iodine‐induced intermolecular heavy‐atom effect to elevate the ¹O₂ generation, are designed and prepared. The nanoparticles are composed of a near‐infrared (NIR) absorbing semiconducting polymer (PCPDTBT) serving as the photosensitizer and source of fluorescence signal, and an iodine‐grafted amphiphilic diblock copolymer (PEG‐PHEMA‐I) serving as the ¹O₂ generation enhancer and nanocarrier. Compared with SPN composed of PEG‐b‐PPG‐b‐PEG and PCPDTBT (SPN‐P), SPN‐I can enhance the ¹O₂ generation by 1.5‐fold. In addition, SPN‐I have high X‐ray attenuation coefficient because of the high density of iodine in PEG‐PHEMA‐I, providing SPN‐I the ability of use with computed tomography (CT) and fluorescence dual‐modal imaging. The study thus provides a simple nanotheranostic platform composed of two components for efficient CT/fluorescence dual‐modal imaging‐guided enhanced PDT.     

Multifunctional Yolk‐in‐Shell Nanoparticles for pH‐triggered Drug Release and Imaging

Multifunctional nanoparticles are synthesized for both pH‐triggered drug release and imaging with radioluminescence, upconversion luminescent, and magnetic resonance imaging (MRI). The particles have a yolk‐in‐shell morphology, with a radioluminescent core, an upconverting shell, and a hollow region between the core and shell for loading drugs. They are synthesized by controlled encapsulation of a radioluminescent nanophosphor yolk in a silica shell, partial etching of the yolk in acid, and encapsulation of the silica with an upconverting luminescent shell. Metroxantrone, a chemotherapy drug, was loaded into the hollow space between X‐ray phosphor yolk and up‐conversion phosphor shell through pores in the shell. To encapsulate the drug and control the release rate, the nanoparticles are coated with pH‐responsive biocompatible polyelectrolyte layers of charged hyaluronic acid sodium salt and chitosan. The nanophosphors display bright luminescence under X‐ray, blue light (480 nm), and near infrared light (980 nm). They also served as T₁ and T₂ MRI contrast agents with relaxivities of 3.5 mM^?1 s^?1 (r₁) and 64 mM^?1s^?1 (r₂). These multifunctional nanocapsules have applications in controlled drug delivery and multimodal imaging.