An NIR‐II Fluorescence/Dual Bioluminescence Multiplexed Imaging for In Vivo Visualizing the Location,Survival, and Differentiation of Transplanted Stem Cells

The in vivo distribution, viability, and differentiation capability of transplanted stem cells are vital for the therapeutic efficacy of stem cell–based therapy. Herein, an NIR‐II fluorescence/dual bioluminescence multiplexed imaging method covering the visible and the second near‐infrared window from 400 to 1700 nm is successfully developed for in vivo monitoring the location, survival, and osteogenic differentiation of transplanted human mesenchymal stem cells (hMSCs) in a calvarial defect mouse model. The exogenous Ag₂S quantum dot–based fluorescence imaging in the second near‐infrared window is applied for visualizing the long‐term biodistribution of transplanted hMSCs. Endogenous red firefly luciferase (RFLuc)‐based bioluminescence imaging (BLI) and the collagen type 1 promoter–driven Gaussia luciferase (GLuc)‐based BLI are employed to report the survival and osteogenic differentiation statuses of the transplanted hMSCs. Meanwhile, by integrating the three imaging channels, multiple dynamic biological behaviors of transplanted hMSCs and the promotion effects of immunosuppression and the bone morphogenetic protein 2 on the survival and osteogenic differentiation of transplanted hMSCs are directly observed. The novel multiplexed imaging method can greatly expand the capability for multifunctional analysis of the fates and therapeutic capabilities of the transplanted stem cells, and aid in the improvement of stem cell–based regeneration therapies and their clinical translation.     

Simultaneous Deep Tracking of Stem Cells by Surface Enhanced Raman Imaging Combined with Single-Cell Tracking by NIR-II Imaging in Myocardial Infarction

Stem cell therapy has been used as a potential approach for the treatment of myocardial infarction (MI) over the last two decades. Imaging cellular behaviors of the transplanted stem cells with deep tissue penetration and high precision imaging modalities is crucial for the clinical translation of stem cell therapy approaches for MI. Herein, a gold nanostar (Au-Star) based second near-infrared window (NIR-II) fluorescence/surface enhanced Raman scattering dual-modal imaging probe (gold nanostar-3.3′-diethylthiatricarbocyanine iodide-silver sulfide nanoparticles, Au-Star-DTTC-Ag₂S NPs, GDS NPs) is designed for labeling and precise tracking of the stem cells. The Ag₂S compartment generates strong NIR-II emission, which compensates for the deficiencies of bioluminescent imaging and enables the dynamic observation of in vivo cellular behavior. Subsequently, the specific Raman signal of Au-Star-DTTC compartment enables high-resolution imaging, which could effectively delineate stem cells from the surrounding normal tissues, even at a single-cell resolution. Using this imaging and tracking approach, it is able to track stem cells in hypodermic and MI models, with high resolution and depth-independent imaging capabilities, which have not been reported in any other cell tracking platform. This two-armed imaging toolkit offers new opportunities for a wide range of mechanistic stem cell therapy investigations in different organs.     

Protamine Functionalized Single‐Walled Carbon Nanotubes for Stem Cell Labeling and In Vivo Raman/Magnetic Resonance/Photoacoustic Triple‐Modal Imaging

Stem cells have shown great potential in regenerative medicine and attracted tremendous interests in recent years. Sensitive and reliable methods for stem cell labeling and in vivo tracking are thus urgently needed. Here, a novel approach to label human mesenchymal stem cells (hMSCs) with single‐walled carbon nanotubes (SWNTs) for in vivo tracking by triple‐modal imaging is presented. It is shown that polyethylene glycol (PEG) functionalized SWNTs conjugated with protamine (SWNT‐PEG‐PRO) exhibit extremely efficient cell entry into hMSCs, without affecting their proliferation and differentiation. The strong inherent resonance Raman scattering of SWNTs is used for in vitro and in vivo Raman imaging of SWNT‐PEG‐PRO‐labeled hMSCs, enabling ultrasensitive in vivo detection of as few as 500 stem cells administrated into mice. On the other hand, the metallic catalyst nanoparticles attached on nanotubes can be utilized as the T2‐contrast agent in magnetic resonance (MR) imaging of SWNT‐labeled hMSCs. Moreover, in vivo photoacoustic imaging of hMSCs in mice is also demonstrated. The work reveals that SWNTs with appropriate surface functionalization have the potential to serve as multifunctional nanoprobes for stem cell labeling and multi‐modal in vivo tracking.     

Ultrastable and Biocompatible NIR‐II Quantum Dots for Functional Bioimaging

Fluorescence bioimaging in the second near‐infrared spectral region (NIR‐II, 1000–1700 nm) can provide advantages of high spatial resolution and large penetration depth, due to low light scattering. However, NIR‐II fluorophores simultaneously possessing high brightness, good stability, and biocompatibility are very rare. Hydrophobic NIR‐II emissive PbS@CdS quantum dots (QDs) are surface‐functionalized, via a silica and amphiphilic polymer (Pluronic F‐127) dual‐layer coating method. The as‐synthesized PbS@CdS@SiO₂@F‐127 nanoparticles (NPs) are aqueously dispersible and possess a quantum yield of ≈5.79%, which is much larger than those of most existing NIR‐II fluorophores. Thanks to the dual‐layer protection, PbS@CdS@SiO₂@F‐127 NPs show excellent chemical stability in a wide range of pH values. The biocompatibility of PbS@CdS@SiO₂@F‐127 NPs is studied, and the results show that the toxicity of the NPs in vivo could be minimal. PbS@CdS@SiO₂@F‐127 NPs are then utilized for in vivo and real‐time NIR‐II fluorescence microscopic imaging of mouse brain. The architecture of blood vessels is visualized and the imaging depth reaches 950 µm. Furthermore, in vivo NIR‐II fluorescence imaging of gastrointestinal tract is achieved, by perfusing PbS@CdS@SiO₂@F‐127 NPs into mice at a rather low dosage. This work illustrates the potential of ultrastable, biocompatible, and bright NIR‐II QDs in biomedical and clinical applications, which require deep tissue imaging.     

Multimodal Magnetic Nanoclusters for Gene Delivery,Directed Migration,and Tracking of Stem Cells

This study develops multimodal magnetic nanoclusters (M‐MNCs) for gene transfer, directed migration, and tracking of human mesenchymal stem cells (hMSCs). The M‐MNCs are designed with 5 nm iron oxide nanoparticles and a fluorescent dye (i.e., Rhodamine B) in the matrix of the Food and Drug Administration approved polymer poly(lactide‐co‐glycolide) using a nanoemulsion method. The synthesized M‐MNCs have a hydrodynamic diameter of ≈150 nm, are internalized by stem cells via endocytosis, and deliver genes with high efficiency. The cellular internalization and gene expression efficiency of the clustered nanoparticles are significantly higher than that of single nanoparticles. The M‐MNC‐labeled hMSCs migrate upon application of a magnetic force and can be visualized by both optical and magnetic resonance (MR) imaging. In animal models, the M‐MNC‐labeled hMSCs are also successfully tracked using optical and MR imaging. Thus, the M‐MNCs not only allow the efficient delivery of genes to stem cells but also the tracking of cells in animal models. Taken together, the results show that this new type of nanocomposite can be of great help in future stem cell research and in the development of cell‐based therapeutic agents.     

Nanocarrier‐Mediated Codelivery of Small Molecular Drugs and siRNA to Enhance Chondrogenic Differentiation and Suppress Hypertrophy of Human Mesenchymal Stem Cells

Cartilage loss is a leading cause of disability among adults, and effective therapy remains elusive. Human mesenchymal stem cells (hMSCs), which have demonstrated self‐renewal and multipotential differentiation, are a promising cell source for cartilage repair. However, the hypertrophic differentiation of the chondrogenically induced MSCs and resulting tissue calcification hinders the clinical translation of MSCs for cartilage repair. Here, a multifunctional nanocarrier based on quantum dots (QDs) is developed to enhance chondrogenic differentiation and suppress hypertrophy of hMSCs simultaneously. Briefly, the QDs are modified with β‐cyclodextrin (β‐CD) and RGD peptide. The resulting nanocarrier is capable of carrying hydrophobic small molecules such as kartogenin in the hydrophobic pockets of conjugated β‐CD to induce chondrogenic differentiation of hMSCs. Meanwhile, via electrostatic interaction the conjugated RGD peptides bind the cargo siRNA targeting Runx2, which is a key regulator of hMSC hypertrophy. Furthermore, due to the excellent photostability of QDs, hMSCs labeled with the nanocarrier can be tracked for up to 14 d after implantation in nude mice. Overall, this work demonstrates the potential of our nanocarrier for inducing and maintaining the chondrogenic phenotype and tracking hMSCs in vivo.     

Development of a Dual‐Modally Traceable Nanoplatform for Cancer Theranostics Using Natural Circulating Cell‐Derived Microparticles in Oral Cancer Patients

Cell‐derived microparticles (MPs), which are biogenic nanosized membrane vesicles that convey bioactive molecules between cells, have exhibited great potential to serve as therapeutic platforms. However, so far, all the MPs used as theranostic vectors in previous studies have been produced in vitro from cell culture supernatants, which is still associated with several concerns regarding practical applications. In this study, circulating MPs (CMPs), which are freshly purified from the peripheral blood of oral squamous cell carcinoma (OSCC) patients, are directly and efficiently embedded with ultrasmall near‐infrared‐fluorescent magnetic quantum dots (Ag₂Se@Mn QDs) via electroporation. By virtue of the superior photostability, favorable biocompatibility, and dual‐mode traceability of Ag₂Se@Mn QD‐labeled CMPs in vivo, the tissue distribution and natural tumor‐targeting behavior of CMPs from OSCC patients are directly visualized in living mice for the first time. Moreover, by simultaneously embedding antitumor siRNA and Ag₂Se@Mn QDs into CMPs derived from OSCC patients, a dual‐modally traceable and actively tumor‐targeted nanoplatform for cancer theranostics is developed. This study reports the first reliable conjugation‐free labeling strategy for in vivo dual‐mode tracking of CMPs harvested from the human body, and, more importantly, reports the development of traceable tumor‐targeted theranostic vectors based on naturally occurring CMPs from cancer patients.     

Multifunctional Upconversion Nanoparticles for Dual‐Modal Imaging‐Guided Stem Cell Therapy under Remote Magnetic Control

Stem cells have generated a great deal of excitement in cell‐based therapies. Here, a unique class of multifunctional nanoparticles (MFNPs) with both upconversion luminescence (UCL) and superparamagnetic properties is used for stem cell research. It is discovered that after being labeled with MFNPs, mouse mesenchymal stem cells (mMSCs) are able to maintain their viability and differentiation ability. In vivo UCL imaging of MFNP‐labeled mMSCs transplanted into animals is carried out, achieving ultrahigh tracking sensitivity with a detection limit as low as ≈10 cells in a mouse. Using both UCL optical and magnetic resonance (MR) imaging approaches, MFNP‐labeled mMSCs are tracked after being intraperitoneally injected into wound‐bearing mice under a magnetic field. The translocation of mMSCs from the injection site to the wound nearby the magnet is observed and, intriguingly, a remarkably improved tissue repair effect is observed as the result of magnetically induced accumulation of stem cells in the wound site. The results demonstrate the use MFNPs as novel multifunctional probes for labeling, in vivo tracking, and manipulation of stem cells, which is promising for imaging guided cell therapies and tissue engineering.     

Multifunctional Biomedical Imaging in Physiological and Pathological Conditions Using a NIR‐II Probe

Compared with imaging in the visible (400–650 nm) and near‐infrared window I (NIR‐I, 650–900 nm) regions, imaging in near‐infrared window II (NIR‐II, 1000–1700 nm) is a highly promising in vivo imaging modality with improved resolution and deeper tissue penetration. Here, a small molecule NIR‐II dye,5,5′‐(1H,5H‐benzo[1,2‐c:4,5‐c′] bis[1,2,5]thiadiazole)‐4,8‐diyl)bis(N,N‐bis(4‐(3‐((tert‐butyldimethylsilyl)oxy)propyl)phenyl) thiophen‐2‐amine), is successfully encapsulated into phospholipid vesicles to prepare a probe CQS1000. The novel NIR‐II probe is studied for in vivo multifunctional biological imaging. The results of this study indicate that the NIR‐II vesicle CQS1000 can noninvasively and dynamically visualize and monitor many physiological and pathological conditions of circulatory systems, including lymphatic drainage and routing, angiogenesis of tumor, and vascular deformity such as arterial thrombus formation and ischemia with high spatial and temporal resolution. More importantly, by virtue of the favorable half‐life of blood circulation of CQS1000, NIR‐II imaging is capable of aiding precise resection of tumor such as osteosarcoma and accelerating the process of lymph node dissection to complete sentinel lymph node biopsy for better decision making during the tumor surgery. Overall, CQS1000 is a highly promising NIR‐II probe for multifunctional biomedical imaging in physiological and pathological conditions, surpassing traditional NIR‐I imaging modality and pathologic assessments for clinical diagnosis and treatment.     

In Vivo Micro‐CT Imaging of Human Mesenchymal Stem Cells Labeled with Gold‐Poly‐l‐Lysine Nanocomplexes

Developing in vivo cell tracking is an important prerequisite for further development of cell‐based therapy. So far, few computed tomography (CT) cell tracking studies have been described due to its notoriously low sensitivity and lack of efficient labeling protocols. A simple method is presented to render human mesenchymal stem cells (hMSCs) sufficiently radiopaque by complexing 40 nm citrate‐stabilized gold nanoparticles (AuNPs) with poly‐l ‐lysine (PLL) and rhodamine B isothiocyanate (RITC). AuNP‐PLL‐RITC labeling does not affect cellular viability, proliferation, or downstream cell differentiation into adipocytes and osteocytes. Labeled hMSCs can be clearly visualized in vitro and in vivo with a micro‐CT scanner, with a detection limit of ≈2 × 10⁴ cells per µL in vivo. Calculated Hounsfield unit values are 2.27 per pg of intracellular Au, as measured with inductively coupled plasma mass spectrophotometry, and are linear over a wide range of cell concentrations. This linear CT attenuation is observed for both naked AuNPs and those that were taken up by hMSCs, indicating that the number of labeled cells can be quantified similar to the use of radioactive or fluorine tracers. This approach for CT cell tracking may find applications in CT image‐guided interventions and fluoroscopic procedures commonly used for the injection of cellular therapeutics.     

Conjugated Polymer Nanodots as Ultrastable Long‐Term Trackers to Understand Mesenchymal Stem Cell Therapy in Skin Regeneration

Stem cell–based therapies hold great promise in providing desirable solutions for diseases that cannot be effectively cured by conventional therapies. To maximize the therapeutic potentials, advanced cell tracking probes are essential to understand the fate of transplanted stem cells without impairing their properties. Herein, conjugated polymer (CP) nanodots are introduced as noninvasive fluorescent trackers with high brightness and low cytotoxicity for tracking of mesenchymal stem cells (MSCs) to reveal their in vivo behaviors. As compared to the most widely used commercial quantum dot tracker, CP nanodots show significantly better long‐term tracking ability without compromising the features of MSCs in terms of proliferation, migration, differentiation, and secretome. Fluorescence imaging of tissue sections from full‐thickness skin wound–bearing mice transplanted with CP nanodot‐labeled MSCs suggests that paracrine signaling of the MSCs residing in the regenerated dermis is the predominant contribution to promote skin regeneration, accompanied with a small fraction of endothelial differentiation. The promising results indicate that CP nanodots could be used as next generation of fluorescent trackers to reveal the currently ambiguous mechanisms in stem cell therapies through a facile and effective approach.     

Ultrasmall Quantum Dots with Broad‐Spectrum Metal Doping Ability for Trimodal Molecular Imaging

Development of efficient targeting nanomaterials is extremely challenging due to the nonspecific accumulation in immune tissues, such as the liver and the spleen. Ultrasmall nanoparticles (USNPs) could possess small molecule‐like in vivo pharmacokinetic profiles, coupled with integrated functions capacity, improving the molecular imaging efficiency, particularly in oncology. For nuclear imaging, radiometals are often incorporated into the structures of USNPs using chelator and chelator‐free strategies. However, the incorporated chelator may change the surface properties and in vivo behavior of UNSPs, while chelator‐free labeling strategies either involve complicated resynthesis or rely on the active properties of the metal ions. Herein, a novel chelator‐free and postsynthetic strategy for broad‐spectrum metal ion attachment is reported. The ultrasmall Ag₂Se quantum dots (QDs) are developed with an active oxygen layer on the surface, allowing for facile incorporation of both active and inert metals with high labeling efficiency. The particles enable fluorescence, magnetic resonance imaging, and positron emission tomography (PET) trimodality imaging. After conjugation with targeting peptide, the probe yields a high tumor‐to‐muscle ratio of nine in PET imaging. Importantly, the QDs are predominantly excreted from body through the renal route within 12 h. This chelator‐free strategy opens an avenue for exploring broad‐spectrum radiometal isotope labeling and USNP‐based renal‐excreting imaging probes.     

PbS/CdS/ZnS Quantum Dots: A Multifunctional Platform for In Vivo Near‐Infrared Low‐Dose Fluorescence Imaging

Over the past decade, near‐infrared (NIR)‐emitting nanoparticles have increasingly been investigated in biomedical research for use as fluorescent imaging probes. Here, high‐quality water‐dispersible core/shell/shell PbS/CdS/ZnS quantum dots (hereafter QDs) as NIR imaging probes fabricated through a rapid, cost‐effective microwave‐assisted cation exchange procedure are reported. These QDs have proven to be water dispersible, stable, and are expected to be nontoxic, resulting from the growth of an outer ZnS shell and the simultaneous surface functionalization with mercaptopropionic acid ligands. Care is taken to design the emission wavelength of the QDs probe lying within the second biological window (1000–1350 nm), which leads to higher penetration depths because of the low extinction coefficient of biological tissues in this spectral range. Furthermore, their intense fluorescence emission enables to follow the real‐time evolution of QD biodistribution among different organs of living mice, after low‐dose intravenous administration. In this paper, QD platform has proven to be capable (ex vivo and in vitro) of high‐resolution thermal sensing in the physiological temperature range. The investigation, together with the lack of noticeable toxicity from these PbS/CdS/ZnS QDs after preliminary studies, paves the way for their use as outstanding multifunctional probes both for in vitro and in vivo applications in biomedicine.     

Photoacoustic Imaging of Embryonic Stem Cell‐Derived Cardiomyocytes in Living Hearts with Ultrasensitive Semiconducting Polymer Nanoparticles

Human embryonic stem cell‐derived cardiomyocytes (hESC‐CMs) have become promising tools to repair injured hearts. To achieve optimal outcomes, advanced molecular imaging methods are essential to accurately track these transplanted cells in the heart. In this study, it is demonstrated for the first time that a class of photoacoustic nanoparticles (PANPs) incorporating semiconducting polymers (SPs) as contrast agents can be used in the photoacoustic imaging (PAI) of transplanted hESC‐CMs in living mouse hearts. This is achieved by virtue of two benefits of PANPs. First, strong photoacoustic (PA) signals and specific spectral features of SPs allow PAI to sensitively detect and distinguish a small number of PANP‐labeled cells (2000) from background tissues. Second, the PANPs show a high efficiency for hESC‐CM labeling without adverse effects on cell structure, function, and gene expression. Assisted by ultrasound imaging, the delivery and engraftment of hESC‐CMs in living mouse hearts can be assessed by PANP‐based PAI with high spatial resolution (≈100 µm). In summary, this study explores and validates a novel application of SPs as a PA contrast agent to track labeled cells with high sensitivity and accuracy in vivo, highlighting the advantages of integrating PAI and PANPs to advance cardiac regenerative therapies.     

Multivalent Aptamer Functionalized Ag2S Nanodots/Hybrid Cell Membrane‐Coated Magnetic Nanobioprobe for the Ultrasensitive Isolation and Detection of Circulating Tumor Cells

Circulating tumor cells (CTCs) play key roles in the development of tumor metastasis. It remains a significant challenge to capture and detect CTCs with high purity and sensitivity from blood samples. Herein, a nanoplatform is developed for the efficient isolation and ultrasensitive detection of CTCs by combining near‐infrared (NIR) multivalent aptamer functionalized Ag₂S nanodots with hybrid cell membrane‐coated magnetic nanoparticles. Multivalent aptamer functionalized Ag₂S nanodots are synthesized using a one‐pot method under mild conditions (60 °C). White blood cell and tumor cell membranes are fused as the hybrid membrane and coated with magnetic nanoparticles, which are further modified with streptavidin (SA). Through the specific interaction of SA‐biotin, the multivalent aptamer‐Ag₂S nanodots are grafted with hybrid cell membrane‐magnetic nanoparticles. Due to the features of hybrid cell membrane modification, multivalent aptamer functionalization, magnetic separation, and NIR fluorescence measurements, the nanoplatform shows sensitive recognition, efficient capture, easy isolation, and sensitive detection of CTCs due to its great enhancement in anti‐interference from background and improvement on binding ability toward CTCs. The capture efficiency and purity for CTCs is as high as 97.63% and 96.96%, respectively. Furthermore, the nanoplatform is successfully applied to the detection of CTCs in blood samples.     

Magnetic/Fluorescent Barcodes Based on Cadmium‐Free Near‐Infrared‐Emitting Quantum Dots for Multiplexed Detection

Magnetic/fluorescent barcodes, which combine quantum dots (QDs) and superparamagnetic nanoparticles in micrometer‐sized host microspheres, are promising for automatic high‐throughput multiplexed biodetection applications and “point of care” biodetection. However, the fluorescence intensity of QDs sharply decreases after addition of magnetic nanoparticles (MNPs) due to absorption by MNPs, and thus, the encoding capacity of QDs becomes more limited. Furthermore, the intrinsic toxicity of cadmium‐based QDs, the most commonly used QD in barcodes, has significant risks to human health and the environment. In this work, to alleviate fluorescence quenching and intrinsic toxicity, cadmium‐free NIR‐emitting CuInS₂/ZnS QDs and Fe₃O₄ MNPs are successfully incorporated into poly(styrene‐co‐maleic anhydride) microspheres by using the Shirasu porous glass membrane emulsification technique. A “single‐wavelength” encoding model is successfully constructed to guide the encoding of NIR QDs with wide emission spectra. Then, a “single‐wavelength” encoding combined with size encoding is used to produce different optical codes by simply changing the wavelength and the intensity of the QDs as well as the size of the barcode microspheres. 48 barcodes are easily created due to the greatly reduced energy transfer between the NIR‐emitting QDs and MNPs. The resulting bifunctional barcodes are also combined with a flow cytometer using one laser for multiplexed detection of five tumor markers in one test. Assays based on these barcodes are significantly more sensitive than non‐magnetic and traditional ELISA assays. Moreover, validating experiments also show good performance of the bifunctional barcodes‐based suspension array when dealing with patient serum samples. Thus, magnetic/fluorescent barcodes based on NIR‐emitting CuInS₂/ZnS QDs are promising for multiplexed bioassay applications.     

Molecular Imaging in the Second Near‐Infrared Window

In the past decade, noticeable progress has been achieved regarding fluorescence imaging in the second near‐infrared (NIR‐II) window. Fluorescence imaging in the NIR‐II window demonstrates superiorities of deep tissue penetration and high spatial and temporal resolution, which are beneficial for profiling physiological processes. Meanwhile, molecular imaging has emerged as an efficient tool to decipher biological activities on the molecular and cellular level. Extending molecular imaging into the NIR‐II window would enhance the imaging performance, providing more detailed and accurate information of the biological system. In this progress report, selected achievements made in NIR‐II molecular imaging are summarized. The organization of this report is based on strategies underlying rational designs of NIR‐II imaging probes, and their applications in molecular imaging are highlighted. This progress report may provide guidance and reference for further development of functional NIR‐II probes designed for high‐performance molecular imaging.     

New Opportunities: Second Harmonic Generation of Boron‐Doped Graphene Quantum Dots for Stem Cells Imaging and Ultraprecise Tracking in Wound Healing

Second harmonic generation (SHG) has recently emerged, having the advantages of no bleaching, no blinking, and no signal saturation, as well as a high signal to‐noise ratio compared to fluorescence. Existing SHG probes are based on heavy metal or organic dye molecules, which have the shortcomings of toxicity, a large size, or photoinstability. To address the urgent need for long‐term tracking and imaging in organisms, boron‐doped graphene quantum dots (B‐GQDs), a highly biocompatible graphene based with a strong and photostable SHG signal is first synthesized and is further applied for stem cell imaging and tracking in wounds. The results demonstrate the possibility of stem cell internalization of B‐GQDs as a SHG probe and show no hindering of the stem cell's central physiological activities such as differentiation. Most importantly, B‐GQDs are successfully tracked in skin tissue in vivo after the labeled mouse mesenchymal stem cells being implanted over 35 days. This work will inspire the development of doped graphene quantum dot materials and promote the broad use of B‐GQDs in future molecular imaging, drug delivery, and stem cell therapy.     

Light‐Activatable Assembled Nanoparticles to Improve Tumor Penetration and Eradicate Metastasis in Triple Negative Breast Cancer

Triple‐negative breast cancer (TNBC) is a kind of aggressive malignancy with fast metastatic behavior. Herein, a nanosystem loaded with a near‐infrared (NIR) agent is developed to achieve chemo‐photothermal combination therapy for inhibiting tumor growth and metastasis in TNBC. The NIR agent of ultrasmall sized copper sulfide nanodots with strong NIR light‐absorbing capability is entrapped into the doxorubicin‐contained temperature‐sensitive polymer‐based nanosystem by a self‐assembled method. The temperature sensitive nanoclusters (TSNCs) can significantly enhance the drug penetration depth and significantly kill the cancer cells under the near‐infrared laser irradiation. Importantly, it is plausible that the tumor penetrating nanosystem combined with NIR laser irradiation can prevent lung and liver metastasis via extermination of the cancer stem cells. The in vivo characteristics, evaluated by photoacoustic imaging, pharmacokinetics, and biodistribution, confirm their feasibility for tumor treatment owing to their long blood circulation time and high tumor uptake. Thanks to the high tumor uptake and highly potent antitumor efficacy, the doxorubicin‐induced cardiotoxicity can be avoided when the TSNC is used. Taken together, it is believed that the nanosystem has excellent potential for clinical translation.     

Development of Therapeutic Small‐Molecule Fluorophore for Cell Transplantation

Cell transplantation holds great promise in regenerative medicine but restricted cell survival and tracking severely limited their therapeutic efficacy. The development of multifunctional agents to simultaneously address these challenges will be very helpful in cytotherapy. Near‐infrared (NIR) imaging is being increasingly used for in vivo cell tracking, but the extensive cell contamination and potential cytotoxicity of current membrane lipophilic dyes severely limit their potentialuse in clinical applications. Here, a novel mitochondrial heptamethine dye, NIR cell protector‐61 (NIRCP‐61), is designed and synthesized via modification of N‐alkyl side chains around a heptamethine core, which maintains the superior fluorescent imaging properties and significantly decreases cell contamination. Further, NIRCP‐61 also significantly alleviates cell damage from acute oxidative stress and improves their therapeutic outcome in multiple animal models. This cytoprotective effect is mediated by evoking the intracellular antioxidant defense mechanisms of nuclear factor erythroid 2‐related factor 2 (Nrf2) and phosphoinositide 3‐kinase/protein kinase B (PI3K/Akt) pathways. NIRCP‐61 is the first NIR agent that simultaneously meets the requirements for both cell tracking and cytoprotection. Therefore, NIRCP‐61 may represent an attractive therapeutic fluorophore for cell transplantation and offers a convenient way to impel potential translation in clinical cell‐based therapies.