Dual‐Modality Surface‐Enhanced Resonance Raman Scattering and Multispectral Optoacoustic Tomography Nanoparticle Approach for Brain Tumor Delineation

Difficulty in visualizing glioma margins intraoperatively remains a major issue in the achievement of gross total tumor resection and, thus, better clinical outcome of glioblastoma (GBM) patients. Here, the potential of a new combined optical + optoacoustic imaging method for intraoperative brain tumor delineation is investigated. A strategy using a newly developed gold nanostar synthesis method, Raman reporter chemistry, and silication method to produce dual‐modality contrast agents for combined surface‐enhanced resonance Raman scattering (SERRS) and multispectral optoacoustic tomography (MSOT) imaging is devised. Following intravenous injection of the SERRS‐MSOT‐nanostars in brain tumor bearing mice, sequential MSOT imaging is performed in vivo and followed by Raman imaging. MSOT is able to accurately depict GBMs three‐dimensionally with high specificity. The MSOT signal is found to correlate well with the SERRS images. Because SERRS enables uniquely sensitive high‐resolution surface detection, it could represent an ideal complementary imaging modality to MSOT, which enables real‐time, deep tissue imaging in 3D. This dual‐modality SERRS‐MSOT‐nanostar contrast agent reported here is shown to enable high precision depiction of the extent of infiltrating GBMs by Raman‐ and MSOT imaging in a clinically relevant murine GBM model and could pave new ways for improved image‐guided resection of brain tumors.     

Engineering Novel Targeted Boron‐10‐Enriched Theranostic Nanomedicine to Combat against Murine Brain Tumors via MR Imaging‐Guided Boron Neutron Capture Therapy

Glioblastoma multiforme (GBM) is a very common type of “incurable” malignant brain tumor. Although many treatment options are currently available, most of them eventually fail due to its recurrence. Boron neutron capture therapy (BNCT) emerges as an alternative noninvasive therapeutic treatment modality. The major challenge in treating GBMs using BNCT is to achieve selective imaging, targeting, and sufficient accumulation of boron‐containing drug at the tumor site so that effective destruction of tumor cells can be achieved without harming the normal brain cells. To tackle this challenge, this study demonstrates for the first time that an unprecedented ¹⁰B‐enriched (96% ¹⁰B enrichment) boron nanoparticle nanomedicine (¹⁰BSGRF NPs) surface‐modified with a Fluorescein isothiocyanate (FITC)‐labeled RGD‐K peptide can pass through the brain blood barrier, selectively target at GBM brain tumor sites, and deliver high therapeutic dosage (50.5 µg ¹⁰B g^?1 cells) of boron atoms to tumor cells with a good tumor‐to‐blood boron ratio of 2.8. The ¹⁰BSGRF NPs not only can enhance the contrast of magnetic resonance (MR) imaging to help diagnose the location/size/progress of brain tumor, but also effectively suppress murine brain tumors via MR imaging‐guided BNCT, prolonging the half‐life of mice from 22 d (untreated group) to 39 d.     

Intelligent Nanocomposites with Intrinsic Blood–Brain‐Barrier Crossing Ability Designed for Highly Specific MR Imaging and Sonodynamic Therapy of Glioblastoma

The blood–brain barrier (BBB) is the most important obstacle to improving the clinical outcomes of diagnosis and therapy of glioblastoma. Thus, the development of a novel nanoplatform that can efficiently traverse the BBB and achieve both precise diagnosis and therapy is of great importance. Herein, an intelligent nanoplatform based on holo‐transferrin (holo‐Tf) with in situ growth of MnO₂ nanocrystals is constructed via a reformative mild biomineralization process. Furthermore, protoporphyrin (ppIX), acting as a sonosensitizer, is then conjugated into holo‐Tf to obtain MnO₂@Tf‐ppIX nanoparticles (TMP). Because of the functional inheritance of holo‐Tf during fabrication, TMP can effectively traverse the BBB for highly specific magnetic resonance (MR) imaging of orthotopic glioblastoma. Clear suppression of tumor growth in a C6 tumor xenograft model is achieved via sonodynamic therapy. Importantly, the experiments also indicate that the TMP nanoplatform has satisfactory biocompatibility and biosafety, which favors potential clinical translation.     

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.     

Photoacoustic‐Guided Surgery with Indocyanine Green‐Coated Superparamagnetic Iron Oxide Nanoparticle Clusters

A common cause of local tumor recurrence in brain tumor surgery results from incomplete surgical resection. Adjunctive technologies meant to facilitate gross total resection have had limited efficacy to date. Contrast agents used to delineate tumors preoperatively cannot be easily or accurately used in the real‐time operative setting. Although multimodal imaging contrast agents are developed to help the surgeon discern tumor from normal tissue in the operating room, these contrast agents are not readily translatable. This study has developed a novel contrast agent comprised solely of two Food and Drug Administration approved components, indocyanine green (ICG) and superparamagnetic iron oxide (SPIO) nanoparticles—with no additional amphiphiles or carrier materials, to enable preoperative detection by magnetic resonance (MR) imaging and intraoperative photoacoustic (PA) imaging. The encapsulation efficiency of both ICG and SPIO within the formulated clusters is ≈100%, and the total ICG payload is 20–30% of the total weight (ICG + SPIO). The ICG–SPIO clusters are stable in physiologic conditions; can be taken up within tumors by enhanced permeability and retention; and are detectable by MR. In a preclinical surgical resection model in mice, following injection of ICG–SPIO clusters, animals undergoing PA‐guided surgery demonstrate increased progression‐free survival compared to animals undergoing microscopic surgery.     

Fluorescence Quenching Nanoprobes Dedicated to In Vivo Photoacoustic Imaging and High‐Efficient Tumor Therapy in Deep‐Seated Tissue

Photoacoustic imaging (PAI) and photoacoustic (PA) therapy have promising applications for treating tumors. It is known that the utilization of high‐absorption‐coefficient probes can selectively enhance the PAI target contrast and PA tumor therapy efficiency in deep‐seated tissue. Here, the design of a probe with the highest availability of optical‐thermo conversion by using graphene oxide (GO) and dyes via π–π stacking interactions is reported. The GO serves as a base material for loading dyes and quenching dye fluorescence via fluorescence resonance energy transfer (FRET), with the one purpose of maximum of PA efficiency. Experiments verify that the designed fluorescence quenching nanoprobes can produce stronger PA signals than the sum of the separate signals generated in the dye and the GO. Potential applications of the fluorescence quenching nanoprobes are demonstrated, dedicating to enhance PA contrast of targets in deep‐seated tissues and tumors in living mice. PA therapy efficiency both in vitro and in vivo by using the fluorescence quenching nanoprobes is found to be higher than with the commonly used PA therapy agents. Taken together, quenching dye fluorescence via FRET will provide a valid means for developing high‐efficiency PA probes. Fluorescence quenching nanoprobes are likely to become a promising candidate for deep‐seated tumor imaging and therapy.     

Preoperative Detection and Intraoperative Visualization of Brain Tumors for More Precise Surgery: A New Dual‐Modality MRI and NIR Nanoprobe

In clinical practice, it is difficult to identify tumor margins during brain surgery due to its inherent infiltrative character. Herein, a unique dual‐modality nanoprobe (Gd‐DOTA‐Ag₂S QDs, referred as Gd‐Ag₂S nanoprobe) is reported, which integrates advantages of the deep tissue penetration of enhanced magnetic resonance (MR) imaging of Gd and the high signal‐to‐noise ratio and high spatiotemporal resolution of fluorescence imaging in the second near‐infrared window (NIR‐II) of Ag₂S quantum dots (QDs). Due to the abundant tumor angiogenesis and the enhanced permeability and retention effect in the tumor, a brain tumor (U87MG) in a mouse model is clearly delineated in situ with the help of the Gd assisted T1 MR imaging and the intraoperative resection of the tumor is precisely accomplished under the guidance of NIR‐II fluorescence imaging of Ag₂S QDs after intravenous injection of Gd‐Ag₂S nanoprobe. Additionally, no histologic changes are observed in the main organs of the mouse after administration of Gd‐Ag₂S nanoprobe for 1 month, indicating the high biocompatibility of the nanoprobe. We expect that such a novel “Detection and Operation” strategy based on Gd‐Ag₂S nanoprobe is promising in future clinical applications.     

Active Targeting Using HER‐2‐Affibody‐Conjugated Nanoparticles Enabled Sensitive and Specific Imaging of Orthotopic HER‐2 Positive Ovarian Tumors

Despite advances in cancer diagnosis and treatment, ovarian cancer remains one of the most fatal cancer types. The development of targeted nanoparticle imaging probes and therapeutics offers promising approaches for early detection and effective treatment of ovarian cancer. In this study, HER‐2 targeted magnetic iron oxide nanoparticles (IONPs) are developed by conjugating a high affinity and small size HER‐2 affibody that is labeled with a unique near infrared dye (NIR‐830) to the nanoparticles. Using a clinically relevant orthotopic human ovarian tumor xenograft model, it is shown that HER‐2 targeted IONPs are selectively delivered into both primary and disseminated ovarian tumors, enabling non‐invasive optical and MR imaging of the tumors as small as 1 mm in the peritoneal cavity. It is determined that HER‐2 targeted delivery of the IONPs is essential for specific and sensitive imaging of the HER‐2 positive tumor since we are unable to detect the imaging signal in the tumors following systemic delivery of non‐targeted IONPs into the mice bearing HER‐2 positive SKOV3 tumors. Furthermore, imaging signals and the IONPs are not detected in HER‐2 low expressing OVCAR3 tumors after systemic delivery of HER‐2 targeted‐IONPs. Since HER‐2 is expressed in a high percentage of ovarian cancers, the HER‐2 targeted dual imaging modality IONPs have potential for the development of novel targeted imaging and therapeutic nanoparticles for ovarian cancer detection, targeted drug delivery, and image‐guided therapy and surgery.     

NIR‐II‐Excited Intravital Two‐Photon Microscopy Distinguishes Deep Cerebral and Tumor Vasculatures with an Ultrabright NIR‐I AIE Luminogen

Intravital fluorescence imaging of vasculature morphology and dynamics in the brain and in tumors with large penetration depth and high signal‐to‐background ratio (SBR) is highly desirable for the study and theranostics of vascular‐related diseases and cancers. Herein, a highly bright fluorophore (BTPETQ) with long‐wavelength absorption and aggregation‐induced near‐infrared (NIR) emission (maximum at ≈700 nm) is designed for intravital two‐photon fluorescence (2PF) imaging of a mouse brain and tumor vasculatures under NIR‐II light (1200 nm) excitation. BTPETQ dots fabricated via nanoprecipitation show uniform size of around 42 nm and a high quantum yield of 19 ± 1% in aqueous media. The 2PF imaging of the mouse brain vasculatures labeled by BTPETQ dots reveals a 3D blood vessel network with an ultradeep depth of 924 µm. In addition, BTPETQ dots show enhanced 2PF in tumor vasculatures due to their unique leaky structures, which facilitates the differentiation of normal blood vessels from tumor vessels with high SBR in deep tumor tissues. Moreover, the extravasation and accumulation of BTPETQ dots in deep tumor (more than 900 µm) is visualized under NIR‐II excitation. This study highlights the importance of developing NIR‐II light excitable efficient NIR fluorophores for in vivo deep tissue and high contrast tumor imaging.     

Effect of Retro‐Inverso Isomer of Bradykinin on Size‐Dependent Penetration of Blood–Brain Tumor Barrier

Retro‐inverso bradykinin (RI‐BK) has better metabolic stability and higher affinity for the BK type 2 (B2) receptor, compared with bradykinin. At low doses, RI‐BK can selectively enhance the permeability of the blood–brain tumor barrier (BBTB) without harming normal brain tissue. In this study, gold nanoparticles (GNPs) of size ranging from 5 to 90 nm are synthesized to assess the optimal size of nanocarriers that achieves maximum brain accumulation after the treatment of RI‐BK. The ability of the GNPs to cross the BBTB is tested in a rat C6 glioma tumor model. The results of inductively coupled plasma–mass spectrometry and transmission electron microscopy indicate that GNPs with size of 70 nm achieve maximum permeability to the glioma. The present study supports the conclusion that RI‐BK can enhance the permeability of BBTB and provides fundamental information for further development of nanomedicines or nanoprobes for glioma therapy.     

Traceable Nanoparticles with Dual Targeting and ROS Response for RNAi‐Based Immunochemotherapy of Intracranial Glioblastoma Treatment

The chemotherapy of glioblastoma is severely hindered by the immunosuppressive tumor microenvironment, especially the tumor growth factor β (TGF‐β), an immunosuppressive cytokine. In this study, it is proposed to employ RNAi‐based immunomodulation to modify the tumor immune microenvironment and improve the effect of chemotherapy. Herein, a nanotheranostic system (Angiopep LipoPCB(Temozolomide+BAP/siTGF‐β), ALBTA) with dual targeting and ROS response is established for intracranial glioblastoma treatment. The traceable nanoparticles exhibit strong siRNA condensation, high drug loading efficiency, good serum stability, and magnetic property. They can efficiently cross the blood–brain barrier and target to glioblastoma cells via receptor‐mediated transcytosis. The zwitterionic lipid (distearoyl phosphoethanol‐amine‐polycarboxybetaine lipid) in ALBTA promotes endosomal/lysosomal escape, and thus enhances the cytotoxicity of temozolomide and improves gene silencing efficiency of siTGF‐β. ALBTA significantly improves the immunosuppressive microenvironment and prolongs the survival time of glioma‐bearing mice. Moreover, ALBTA can be accurately traced by MRI in brain tumors. The study indicates that this immunochemotherapeutic platform can serve as a flexible and powerful synergistic system for treatment with brain tumors as well as other brain diseases in central nervous system.     

A deep learning model integrating convolution neural network and multiple kernel K means clustering for segmenting brain tumor in magnetic resonance images

In medical imaging, segmenting brain tumor becomes a vital task, and it provides a way for early diagnosis and treatment. Manual segmentation of brain tumor in magnetic resonance (MR) images is a time‐consuming and challenging task. Hence, there is a need for a computer‐aided brain tumor segmentation approach. Using deep learning algorithms, a robust brain tumor segmentation approach is implemented by integrating convolution neural network (CNN) and multiple kernel K means clustering (MKKMC). In this proposed CNN‐MKKMC approach, classification of MR images into normal and abnormal is performed by CNN algorithm. At next, MKKMC algorithm is employed to segment the brain tumor from the abnormal brain image. The proposed CNN‐MKKMC algorithm is evaluated both visually and objectively in terms of accuracy, sensitivity, and specificity with the existing segmentation methods. The experimental results demonstrate that the proposed CNN‐MKKMC approach yields better accuracy in segmenting brain tumor with less time cost.     

In Vivo MR Imaging of Glioma Recruitment of Adoptive T‐Cells Labeled with NaGdF4‐TAT Nanoprobes

Adoptive T lymphocyte immunotherapy is one of the most promising methods to treat residual lesions after glioma surgery. However, the fate of the adoptively transferred T‐cells in vivo is unclear, hampering the understanding of this emerging therapy. Thus, it is highly desirable to develop noninvasive and quantitative in vivo tracking of these T‐cells to glioma for better identification of the migratory fate and to provide objective evaluation of outcomes of adoptive T‐cell immunotherapy targeting glioma. In this work, ultrasmall T₁ MR‐based nanoprobes, NaGdF₄‐TAT, as molecular probes with high longitudinal relaxivity (8.93 mm ^?1 s^?1) are designed. By means of HIV‐1 transactivator (TAT) peptides, nearly 95% of the adoptive T‐cells are labeled with the NaGdF₄‐TAT nanoprobes without any measurable side effects on the labeled T‐cells, which is remarkably superior to that of the control fluorescein isothiocyanate‐NaGdF₄ concerning labeling efficacy. Labeled adoptive T‐cell clusters can be sensitively tracked in an orthotopic GL261‐glioma model 24 h after intravenous infusion of 10⁷ labeled T‐cells by T₁‐weighted MR imaging. Both in vitro and in vivo experiments show that the NaGdF₄‐TAT nanoprobes labeling of T‐cells may be a promising method to track adoptive T‐cells to improve our understanding of the pathophysiology in adoptive immunotherapy for gliomas.     

Split‐GFP: SERS Enhancers in Plasmonic Nanocluster Probes

The assembly of plasmonic metal nanoparticles into hot spot surface‐enhanced Raman scattering (SERS) nanocluster probes is a powerful, yet challenging approach for ultrasensitive biosensing. Scaffolding strategies based on self‐complementary peptides and proteins are of increasing interest for these assemblies, but the electronic and the photonic properties of such hybrid nanoclusters remain difficult to predict and optimize. Here, split‐green fluorescence protein (sGFP) fragments are used as molecular glue and the GFP chromophore is used as a Raman reporter to assemble a variety of gold nanoparticle (AuNP) clusters and explore their plasmonic properties by numerical modeling. It is shown that GFP seeding of plasmonic nanogaps in AuNP/GFP hybrid nanoclusters increases near‐field dipolar couplings between AuNPs and provides SERS enhancement factors above 10⁸. Among the different nanoclusters studied, AuNP/GFP chains allow near‐infrared SERS detection of the GFP chromophore imidazolinone/exocyclic C?C vibrational mode with theoretical enhancement factors of 10⁸–10⁹. For larger AuNP/GFP assemblies, the presence of non‐GFP seeded nanogaps between tightly packed nanoparticles reduces near‐field enhancements at Raman active hot spots, indicating that excessive clustering can decrease SERS amplifications. This study provides rationales to optimize the controlled assembly of hot spot SERS nanoprobes for remote biosensing using Raman reporters that act as molecular glue between plasmonic nanoparticles.     

NeXt for neuro‐radiosurgery: A fully automatic approach for necrosis extraction in brain tumor MRI using an unsupervised machine learning technique

Stereotactic neuro‐radiosurgery is a well‐established therapy for intracranial diseases, especially brain metastases and highly invasive cancers that are difficult to treat with conventional surgery or radiotherapy. Nowadays, magnetic resonance imaging (MRI) is the most used modality in radiation therapy for soft‐tissue anatomical districts, allowing for an accurate gross tumor volume (GTV) segmentation. Investigating also necrotic material within the whole tumor has significant clinical value in treatment planning and cancer progression assessment. These pathological necrotic regions are generally characterized by hypoxia, which is implicated in several aspects of tumor development and growth. Therefore, particular attention must be deserved to these hypoxic areas that could lead to recurrent cancers and resistance to therapeutic damage. This article proposes a novel fully automatic method for necrosis extraction (NeXt), using the Fuzzy C‐Means algorithm, after the GTV segmentation. This unsupervised Machine Learning technique detects and delineates the necrotic regions also in heterogeneous cancers. The overall processing pipeline is an integrated two‐stage segmentation approach useful to support neuro‐radiosurgery. NeXt can be exploited for dose escalation, allowing for a more selective strategy to increase radiation dose in hypoxic radioresistant areas. Moreover, NeXt analyzes contrast‐enhanced T1‐weighted MR images alone and does not require multispectral MRI data, representing a clinically feasible solution. This study considers an MRI dataset composed of 32 brain metastatic cancers, wherein 20 tumors present necroses. The segmentation accuracy of NeXt was evaluated using both spatial overlap‐based and distance‐based metrics, achieving these average values: Dice similarity coefficient 95.93% ± 4.23% and mean absolute distance 0.225 ± 0.229 (pixels).     

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.     

A GSH‐Gated DNA Nanodevice for Tumor‐Specific Signal Amplification of microRNA and MR Imaging–Guided Theranostics

Developing tumor‐responsive diagnosis and therapy strategies for tumor theranostics is still a challenge owing to their high accuracy and specificity. Herein, an AND logic gated–DNA nanodevice, based on the fluorescence nucleic acid probe and polymer‐modified MnO₂ nanosheets, for glutathione (GSH)‐gated miRNA‐21 signal amplification and GSH‐activated magnetic resonance (MR) imaging–guided chemodynamic therapy (CDT) is reported. In the presence of overexpressed miRNA and GSH (tumor cells), the nanodevice can be in situ activated and release significantly amplified fluorescence signals and MR signals. Conversely, the fluorescence signal is quenched and MR signal remains at the background level with low miRNA and GSH (normal cells), efficiently reducing the false‐positive signals by more than 50%. Under the guide of miRNA profiling and MR imaging, the tumor‐responsive hydroxyl radical ( · OH) can effectively kill tumor cells. Furthermore, the nanodevice shows catalase‐like activity and glucose oxidase–like activity with the performance of O₂ production and glucose consumption. This is the first time to fabricate a tumor‐responsive theranostic DNA nanodevice with tumor‐specific signal amplification of microRNA and GSH‐activated MR imaging for CDT, potential hypoxia relief and starvation therapy, which provides a new insight for designing smart theranostic strategies.     

A New Co‐P Nanocomposite with Ultrahigh Relaxivity for In Vivo Magnetic Resonance Imaging‐Guided Tumor Eradication by Chemo/Photothermal Synergistic Therapy

Design of new nanoagents that intrinsically have both diagnostic imaging and therapeutic capabilities is highly desirable for personalized medicine. In this work, a novel nanotheranostic agent is fabricated based on polydopamine (PDA)‐functionalized Co‐P nanocomposites (Co‐P@PDA) for magnetic resonance imaging (MRI)‐guided combined photothermal therapy and chemotherapy. The ultrahigh relaxivity of 224.61 mm ^?1 s^?1 can enable Co‐P@PDA to be applied as an excellent contrast agent for MRI in vitro and in vivo, providing essential and comprehensive information for tumor clinical diagnosis. Moreover, Co‐P@PDA exhibit excellent photothermal performance owing to the strong near‐infrared (NIR) absorbance of both Co‐P nanocomposite and PDA. Highly effective ablation of tumors is achieved in a murine tumor model because the NIR laser not only induces photothermal effects but also triggers the chemotherapeutic drug on‐demand release, which endows the Co‐P@PDA with high curative effects but little toxicity and few side effects. These findings demonstrate that Co‐P@PDA are promising agents for highly effective and precise antitumor treatment and warrant exploration as novel theranostic nanoagents with good potential for future clinical translation.     

Self‐Assembling Endogenous Biliverdin as a Versatile Near‐Infrared Photothermal Nanoagent for Cancer Theranostics

Photothermal nanomaterials that integrate multimodal imaging and therapeutic functions provide promising opportunities for noninvasive and targeted diagnosis and treatment in precision medicine. However, the clinical translation of existing photothermal nanoagents is severely hindered by their unclear physiological metabolism, which makes them a strong concern for biosafety. Here, the utilization of biliverdin (BV), an endogenic near‐infrared (NIR)‐absorbing pigment with well‐studied metabolic pathways, to develop photothermal nanoagents with the aim of providing efficient and metabolizable candidates for tumor diagnosis and therapy, is demonstrated. It is shown that BV nanoagents with intense NIR absorption, long‐term photostability and colloidal stability, and high photothermal conversion efficiency can be readily constructed by the supramolecular multicomponent self‐assembly of BV, metal‐binding short peptides, and metal ions through the reciprocity and synergy of coordination and multiple noncovalent interactions. In vivo data reveal that the BV nanoagents selectively accumulate in tumors, locally elevate tumor temperature under mild NIR irradiation, and consequently induce efficient photothermal tumor ablation with promising biocompatibility. Furthermore, the BV nanoagents can serve as a multimodal contrast for tumor visualization through both photoacoustic and magnetic resonance imaging. BV has no biosafety concerns, and thereby offers a great potential in precision medicine by integrating multiple theranostic functions.     

Smart‐Dust‐Nanorice for Enhancement of Endogenous Raman Signal,Contrast in Photoacoustic Imaging,and T2‐Shortening in Magnetic Resonance Imaging

Raman microspectroscopy provides chemo‐selective image contrast, sub‐micrometer resolution, and multiplexing capabilities. However, it suffers from weak signals resulting in image‐acquisition times of up to several hours. Surface‐enhanced Raman scattering (SERS) can dramatically enhance signals of molecules in close vicinity of metallic surfaces and overcome this limitation. Multimodal, SERS‐active nanoparticles are usually labeled with Raman marker molecules, limiting SERS to the coating material. In order to realize multimodal imaging while acquiring the rich endogenous vibronic information of the specimen, a core–shell particle based on “Nanorice”, where a spindle‐shaped iron oxide core is encapsulated by a closed gold shell, is developed. An ultrathin layer of silica prevents agglomeration and unwanted chemical interaction with the specimen. This approach provides Raman signal enhancement due to plasmon resonance effects of the shell while the optical absorption in the near‐infrared spectral region provides contrast in photoacoustic tomography. Finally, T2‐relaxation of a magnetic resonance imaging (MRI) experiment is altered by taking advantage of the iron oxide core. The feasibility for Raman imaging is evaluated by nearfield simulations and experimental studies on the primate cell line COS1. MRI and photoacoustics are demonstrated in agarose phantoms illustrating the promising translational nature of this strategy for clinical applications in radiology.