Symmetry-Breaking of Nanoparticle Surface Function Via Conformal DNA Design.

Asymmetric surface functionalization of complex nanoparticles to control their directional self-assembly remains a considerable challenge. Here, we demonstrated a conformal DNA design strategy for flexible remodeling of the surface of complex nanoparticles, taking Au nanobipyramids (AuNBPs) as a model. We sheathed one or both tips of AuNBPs into conformal DNA origami with an exceptionally accurate orientation control. Such asymmetrically and symmetrically distributed surface patches possess regioselective, sequence, and site-specific DNA binding capabilities. As a result, we realized a series of prototypical multicomponent "colloidal molecules" made of AuNBPs and Au nanospheres (AuNSs) with defined directionality and number of "bonding valence" as well as 1D and 3D hierarchical assemblies, e.g., inverse core-satellites of AuNBPs and AuNSs, side-by-side and tip-to-tip linear assemblies of AuNBPs, and 3D helical superstructures of AuNBPs with tunable twists. These findings inspire new opportunities for nanoparticle surface engineering and the high-order self-assembly of nanoarchitectures with higher complexity and broadened functionalities.

Rational Design of NIR-II Ratiometric Fluorescence Probes for Accurate Bioimaging and Biosensing In Vivo.

Intravital fluorescence imaging in the second near-infrared window (NIR-II, 900-1700 nm) has emerged as a promising method for non-invasive diagnostics in complex biological systems due to its advantages of less background interference, high tissue penetration depth, high imaging contrast, and sensitivity. However, traditional NIR-II fluorescence imaging, which is characterized by the "always on" or "turn on" mode, lacks the ability of quantitative detection, leading to low reproducibility and reliability during bio-detection. In contrast, NIR-II ratiometric fluorescence imaging can realize quantitative and reliable analysis and detection in vivo by providing reference signals for fluorescence correction, generating new opportunities and prospects during in vivo bioimaging and biosensing. In this review, the current design strategies and sensing mechanisms of NIR-II ratiometric fluorescence probes for bioimaging and biosensing applications are systematically summarized. Further, current challenges, future perspectives and opportunities for designing NIR-II ratiometric fluorescence probes are also discussed. It is hoped that this review can provide effective guidance for the design of NIR-II ratiometric fluorescence probes and promote its adoption in reliable biological imaging and sensing in vivo.

Programmed Remodeling of the Tumor Milieu to Enhance NK Cell Immunotherapy Combined with Chemotherapy for Pancreatic Cancer.

Natural killer (NK) cell-based adoptive immunotherapy has demonstrated encouraging therapeutic effects in clinical trials for hematological cancers. However, the effectiveness of treatment for solid tumors remains a challenge due to insufficient recruitment and infiltration of NK cells into tumor tissues. Herein, a programmed nanoremodeler (DAS@P/H/pp) is designed to remodel dense physical stromal barriers and for dysregulation of the chemokine of the tumor environment to enhance the recruitment and infiltration of NK cells in tumors. The DAS@P/H/pp is triggered by the acidic tumor environment, resulting in charge reversal and subsequent hyaluronidase (HAase) release. HAase effectively degrades the extracellular matrix, promoting the delivery of immunoregulatory molecules and chemotherapy drugs into deep tumor tissues. In mouse models of pancreatic cancer, this nanomediated strategy for the programmed remodeling of the tumor microenvironment significantly boosts the recruitment of NK92 cells and their tumor cell-killing capabilities under the supervision of multiplexed near-infrared-II fluorescence.

Multichannel-optical imaging for in vivo evaluating the safety and therapeutic efficacy of stem cells in tumor model in terms of cell tropism, proliferation and NF-κB activity.

Stem cell-based cancer treatment has garnered significant attention, yet its safety and efficacy remain incompletely understood. The nuclear factor-kappa B (NF-κB) pathway, a critical signaling mechanism involved in tumor growth, angiogenesis, and invasion, serves as an essential metric for evaluating the behavior of stem cells in tumor models. Herein, we report the development of a triple-channel imaging system capable of simultaneously monitoring the tropism of stem cells towards tumors, assessing tumor proliferation, and quantifying tumor NF-κB activity. In this system, we generated a CRISPR-Cas9 gene-edited human glioblastoma cell line, GE-U87-MG, which provided a reliable readout of the proliferation and NF-κB activity of tumors by EF1α-RFLuc- and NF-κB-GLuc-based bioluminescent imaging, respectively. Additionally, near infrared-II emitting Tat-PEG-AgAuSe quantum dots were developed for tracking of stem cell tropism towards tumor. In a representative case involving human mesenchymal stem cells (hMSCs), multichannel imaging revealed no discernible effect of hMSCs on the proliferation and NF-κB activity of GE-U87-MG tumors. Moreover, hMSCs engineered to overexpress the necrosis factor-related apoptosis-inducing ligand were able to inhibit NF-κB activity and growth of GE-U87-MG in vivo. Taken together, our imaging system represents a powerful and feasible approach to evaluating the safety and therapeutic efficacy of stem cells in tumor models.

Planar oligomerization of reconfigurable gold nanorod dimers.

Reconfigurable chiral plasmonic complexes are fabricated by planar assembly of multiple individual gold nanorod dimers using DNA origami templates. Additionally, each chiral center can be controlled to switch among achiral, left-handed, and right-handed states. We demonstrate that their overall circular dichroism is determined by the coupling of individual chiral centers and is heavily influenced by the precise number and arrangement of these centers. Our study offers a novel self-assembly method for constructing intricate and dynamic chiral plasmonics as well as investigating the interactions among several plasmonic chiral centers.

Interface-Mediation-Enabled High-Performance Near-Infrared AgAuSe Quantum Dot Light-Emitting Diodes.

Near-infrared (NIR) quantum dot (QD) light-emitting diodes (LEDs) (NIR-QLEDs) for recognition and tracking applications underpin the future of night-vision technology. However, the performance of environmentally benign materials and devices has lagged far behind that of their Pb-containing counterparts. In this study, we demonstrate the superior performance of NIR-QLEDs based on efficient AgAuSe QDs with contact interface mediation. Consequently, we reveal that using cysteamine-treated QD film contact heterointerfaces can effectively eliminate contact defects in devices and preserve their excellent emissive properties. Additionally, the dipole moment orientation of the coordinated additives is inverse of the heterojunction potential difference, simultaneously blocking electrons and enhancing hole injection in operando, optimizing the LED charge injection balance. These devices exhibit a high external quantum efficiency (EQE) and a power conversion efficiency (PCE) of 15.8 and 12.7% at 1046 nm, respectively, a sub-band gap turn-on voltage of 0.9 V, and a low current density (over 10% of the EQE from 0.0017 to 0.31 mA cm-2). These are the highest EQE and PCE values ever reported for environmentally benign NIR-QLEDs. The results of this study can provide a general strategy for the practical application of QDs in electroluminescent devices.

Tailoring Near-Infrared-IIb Fluorescence of Thulium(III) by Nanocrystal Structure Engineering.

Currently, mainstream lanthanide probes with fluorescence located in the second near-infrared subwindow of 1500-1700 nm (NIR-IIb) are predominantly Er(III)-based nanoparticles (NPs). Here we report a newly developed NIR-IIb fluorescent nanoprobe, α-Tm NP (cubic-phase NaYF4@NaYF4:Tm@NaYF4), with an emission at 1630 nm. We activate the 1630 nm emission of Tm(III) in α-Tm NP through the large spread of the Stark split sublevels induced by the crystal-field effect of the α-NaYF4 host. Further, we systematically investigated the effect of crystalline structure of the host NaYF4 NP (cubic phase (α) or hexagonal phase (ß)), the type and concentrations of dopants (Yb(III), Tm(III), and Ca(II) ions) in the α-phase host, and the thicknesses of the interlayer and inert shell on the NIR-IIb fluorescence of Tm(III). The ultimate nanostructure presents a significant enhancement factor of the NIR-IIb photoluminescence intensity of Tm(III) up to ∼315. With this bright NIR-IIb fluorescent nanoprobe, we demonstrate high-spatial-resolution time-coursing imaging of breast cancer bone metastasis.

Unveiling the energy transfer mechanism between aqueous colloidal NIR-II quantum dots and water.

Hydrophilic semiconductor quantum dots (QDs) with emission in the second near-infrared window (NIR-II) have been widely studied in bioimaging applications. In such cases, QDs are usually dispersed in water. As is known, water has strong absorbance in the NIR-II region. However, investigations on the interaction between NIR-II emitters and water molecules are ignored in previous studies. Herein, we synthesized a series of mercaptoundecanoic acid-coated silver sulfide (Ag2S/MUA) QDs with various emissions that partially or completely overlapped with the absorbance of water at 1200 nm. By constructing a hydrophobic interface of cetyltrimethylammonium bromide (CTAB) with MUA on the Ag2S QDs surface via forming an ionic bond, significant enhancement of Ag2S QDs photoluminescence (PL) intensity was observed, as well as a prolonged lifetime. These findings suggest that there is an energy transfer between Ag2S QDs and water in addition to the classical resonance absorption. Transient absorption and fluorescence spectra results revealed that the increased PL intensities and lifetime of Ag2S QDs originated from the suppressed energy transfer from Ag2S QDs to the water due to the CTAB bridged hydrophobic interfaces. This discovery is important for a deeper understanding of the photophysical mechanisms of QDs and their applications.

Multiscale NIR-II Imaging-Guided Brain-Targeted Drug Delivery Using Engineered Cell Membrane Nanoformulation for Alzheimer's Disease Therapy.

Effective drug delivery in the central nervous system (CNS) needs to have long blood-circulation half-lives, to pass through the blood-brain barrier (BBB), and subsequently to be taken up by target cells. Herein, a traceable CNS delivery nanoformulation (RVG-NV-NPs) is developed by encapsulating bexarotene (Bex) and AgAuSe quantum dots (QDs) within Lamp2b-RVG-overexpressed neural stem cell (NSC) membranes. The high-fidelity near-infrared-II imaging by AgAuSe QDs offers a possibility of in vivo monitoring the multiscale delivery process of the nanoformulation from the whole-body to the single-cell scale. It was revealed the synergy of acetylcholine receptor-targeting of RVG and the natural brain-homing and low immunogenicity of NSC membranes prolong the blood circulation, facilitate BBB crossing and nerve cell targeting of RVG-NV-NPs. Thus, in Alzheimer's disease (AD) mice, the intravenous delivery of as low as 0.5% of oral dose Bex showed highly effective up-regulation of the apolipoprotein E expression, resulting rapid alleviation of ∼40% ß-amyloid (Aß) level in the brain interstitial fluid after a single dose administration. The pathological progression of Aß in AD mice is completely suppressed during a 1 month treatment, thus effectively protecting neurons from Aß-induced apoptosis and maintaining the cognitive abilities of AD mice.

Multifunctional Nano-Biomaterials for Cancer Therapy via Inducing Enhanced Immunogenic Cell Death.

Immunotherapy is considered to be one of the most promising methods to overcome cancer. Immunogenic cell death (ICD), as a special form of cell death that can trigger an antitumor immune response, has attracted increasing attention for cancer immunotherapy. Presently, ICD-mediating immunotherapy needs to overcome many hurdles including a lack of targeted delivery systems for ICD inducers, insufficient antitumor immunity, and the immunosuppressive tumor microenvironment. Recent research has demonstrated that nano-biomaterials exhibit unique biochemphysical properties at the nanoscale, providing a prospective approach to overcoming these obstacles. In this review, the authors first survey the occurrence, processes, and detection methods of ICD. Subsequently, the recent advances of nano-biomaterials applied to enhance ICD according to the key steps in the process of ICD, particularly with a focus on the mechanisms and lifting schemes are investigated. Finally, based on the achievement in the representative studies, the prospects and challenges of nanotechnology in ICD for cancer therapy are discussed to enable clinical translation.

An oral ratiometric NIR-II fluorescent probe for reliable monitoring of gastrointestinal diseases in vivo.

Early monitoring of gastrointestinal diseases via orally delivered NIR-II ratiometric fluorescent probes represents a promising noninvasive diagnostic modality, but is challenging due to the limitation of harsh digestive environment. Here, we report a single-component NIR-II ratiometric molecular nanoprobe (LC-1250 NP) to monitor gastrointestinal disease with high specificity to its biomarker H2O2 via oral administration. LC-1250 NP displays stable fluorescence in the channel of 1250 long-pass (F1250LP) before and after the gastrointestinal disease detection as the reference, while it presents significantly enhanced fluorescence signal in the response channel of 1150 nm short-pass (F1150SP) in diseased gastrointestinal environment due to the intramolecular cyclization of LC-1250 molecules activated by H2O2. The fluorescence ratio (F1150SP/F1250LP) increases linearly with the concentration of H2O2 with a low detection limit of 20 nM. Therefore, when delivered orally, LC-1250 NP can accurately map the diseased areas and surmount the false-positive interference from biological heterogeneity by NIR-II ratiometric fluorescence imaging, providing sensitive and reliable evaluation for the progress of gastroenteritis.

Single-particle fluorescence tracking combined with TrackMate assay reveals highly heterogeneous and discontinuous lysosomal transport in freely orientated axons.

Axonal transport plays a significant role in the establishment of neuronal polarity, axon growth, and synapse formation during neuronal development. The axon of a naturally growing neuron is a highly complex and multifurcated structure with a large number of bends and branches. Nowadays, the study of dynamic axonal transport in morphologically complex neurons is greatly limited by the technological barrier. Here, a sparse gene transfection strategy was developed to locate fluorescent mCherry in the lysosome of primary neurons, thus enabling us to track the lysosome-based axonal transport with a single-particle resolution. Thereby, several axonal transport models were observed, including the forward or backward transport model, stop-and-go model, repeated back-and-forth transport model, and cross-branch transport model. Then, the accurate single-particle velocity quantification by TrackMate revealed a highly heterogeneous and discontinuous transportation process of lysosome-based axonal transport in freely orientated axons. And, multiple physical factors, such as the axonal structure and the size of particles, were disclosed to affect the velocity of particle transporting in freely orientated axons. The combined single-particle fluorescence tracking and TrackMate assay can be served as a facile tool for evaluating axonal transport in neuronal development and axonal transport-related diseases.

Finite Assembly of Three-Dimensional DNA Hierarchical Nanoarchitectures through Orthogonal and Directional Bonding.

Reliable orthogonal bonding with precise and flexible orientation control would be ideal for building finite complex nanostructures via self-assembly. Employing a three-dimensional (3D) DNA origami, hexagonal prism DNA origami (HDO), as building block, we demonstrate it is practical to construct finite hierarchical nanoarchitectures with complicated conformations through orthogonal and directional bonding. The as-designed HDO building block has twelve prescribed directional valences in 3D space and each of them supports two opposite orientations, yielding the capability to generate abundant directional bonding. Meanwhile, we minimize the thorny non-specific interactions among HDOs and enable the orthogonal bonding between any two valences based on self-similar designing. Consequently, various hierarchical nanostructures are prepared at will simply by the combination of HDOs with appropriate valences. We believe this route towards hierarchically assembly is inspiring and hope it will facilitate the fabrication of functional superstructures.

Au-Doped Ag2 Te Quantum Dots with Bright NIR-IIb Fluorescence for In Situ Monitoring of Angiogenesis and Arteriogenesis in a Hindlimb Ischemic Model.

Fluorescence located in 1500-1700 nm (denoted as the near-infrared IIb window, NIR-IIb) has drawn great interest for bioimaging, owing to its ultrahigh tissue penetration depth and spatiotemporal resolution. Therefore, NIR-IIb fluorescent probes with high photoluminescence quantum yield (PLQY) and stability along with high biocompatibility are urgently pursued. Herein, a novel NIR-IIb fluorescent probe of Au-doped Ag2 Te (Au:Ag2 Te) quantum dots (QDs) is developed via a facile cation exchange method. The Au dopant concentration in the Ag2 Te QDs is tunable from 0% to 10% by controlling the ratio of supplied Au precursor to Ag2 Te QDs, resulting in a wide range of PL emission in the NIR-IIb window and a much-enhanced PL intensity. After surface modification, the Au:Ag2 Te QDs possess bright NIR-IIb emission, high colloidal stability and photostability, and decent biocompatibility. Further, in vivo monitoring of the process of angiogenesis and arteriogenesis in an ischemic hindlimb is successfully performed.

Activatable Rare Earth Near-Infrared-II Fluorescence Ratiometric Nanoprobes.

Rational design of efficient lanthanide-doped down-shifting nanoparticles (DSNPs) has attracted tremendous attention. However, energy loss was inevitable in the multiple Ln3+ doping systems owing to complex energy migration processes. Here, an efficient NaErF4@NaYF4@NaYF4:10%Nd@NaYF4 DSNP was tactfully designed, in which a buffer layer of NaYF4 was modulated to restrict the interionic energy migration between Er3+ and Nd3+; meanwhile, the surface defects were passivated by an outermost layer of NaYF4. Therefore, the as-prepared DSNPs exhibited two intensive near-infrared-II fluorescence emissions of 1525 nm from Er3+ and 1060 nm from doped Nd3+ under 808 nm excitation. Further, a novel ratiometric nanoprobe NaErF4@NaYF4@NaYF4:10%Nd@NaYF4@A1094 was fabricated by coupling an organic dye of A1094 onto the DSNP surface to quench the 1060 nm emission by the efficient Förster resonance energy transfer, while emission at 1525 nm retained. Thereafter, these activatable ratiometric nanoprobes were used for rapid and sensitive detection of peroxynitrite (ONOO-) in vivo.

Assembling gold nanobipyramids into chiral plasmonic nanostructures with DNA origami.

Herein, we report the assembly of gold nanobipyramids (AuNBPs) into static and dynamic chiral plasmonic nanostructures via DNA origami. Compared with conventional chiral dimers of gold nanorods (AuNRs), AuNBP dimers exhibit more intriguing chiroptical responses, suggesting that they could be a superior alternative for constructing chiral plasmonic nanostructures for biosensing.

Whole-Body Fluorescence Imaging in the Near-Infrared Window.

Fluorescence imaging is one of the most widely used in vivo imaging methods for both fundamental research and clinical practice. Due to the reduced photon scattering, absorption, and autofluorescence in tissues, the emerging near-infrared (NIR) imaging (650-1700 nm) can afford deep tissue imaging with high spatiotemporal resolution and in vivo report the anatomical structures as well as the physiological activities in a whole-body level. Here, we give a brief introduction to fluorescence imaging in the first NIR (NIR-I, 650-950 nm) and second NIR (NIR-II, 1000-1700 nm) windows, summarize the recently developed NIR fluorophores and their applications in whole-body vascular system imaging, precision cancer theranostics, and regenerative medicine. Finally, the clinical applications and future prospects of in vivo NIR fluorescence imaging are also discussed.

Colloidal Alloyed Quantum Dots with Enhanced Photoluminescence Quantum Yield in the NIR-II Window.

Semiconductor quantum dots (QDs) with photoluminescence (PL) emission at 900-1700 nm (denoted as the second near-infrared window, NIR-II) exhibit much-depressed photon absorption and scattering, which has stimulated extensive researches in biomedical imaging and NIR devices. However, it is very challenging to develop NIR-II QDs with a high photoluminescence quantum yield (PLQY) and excellent biocompatibility. Herein, we designed and synthesized an alloyed silver gold selenide (AgAuSe) QD with a bright emission from 820 to 1170 nm and achieved a record absolute PLQY of 65.3% at 978 nm emission among NIR-II QDs without a toxic element and a long lifetime of 4.58 µs. It is proved that the high PLQY and long lifetime are mainly attributed to the prevented nonradiative transition of excitons, probably resulted from suppressing cation vacancies and crystal defects from the high mobility of Ag ions by alloying Au atoms. These high-PLQY QDs with nontoxic heavy metal exhibit great application potential in bioimaging, light emitting diodes (LEDs), and photovoltaic devices.

A Nanoformulation-Mediated Multifunctional Stem Cell Therapy with Improved Beta-Amyloid Clearance and Neural Regeneration for Alzheimer's Disease.

Alzheimer's disease (AD) is a common dementia that is currently incurable. The existing treatments can only moderately relieve the symptoms of AD to slow down its progress. How to achieve effective neural regeneration to ameliorate cognitive impairments is a major challenge for current AD treatment. Here, the therapeutic potential of a nanoformulation-mediated neural stem cell (NSC) therapy capable of simultaneous Aß clearance and neural regeneration is investigated in a murine model. Genetically engineered NSCs capable of stably and continuously expressing neprilysin (NEP) are developed to enhance Aß degradation and NSC survival in the brain. A PBAE-PLGA-Ag2 S-RA-siSOX9 (PPAR-siSOX9) nanoformulation with high gene/drug deliverability is synthesized to overcome AD microenvironment-associated adverse effects and to promote neuronal differentiation of the NEP-expressing NSCs. For achieving accurate stereotactic transplantation, Ag2 S quantum-dot-based fluorescence imaging is used to guide NSC transplantation in real time. This strategy shows numerous benefits, including efficient and long-lasting Aß degradation, improved neural regeneration, and accurate cell transplantation. It is shown that a single administration of this therapy achieves long-term efficacy (6 months) with respect to memory reversal and improvement of learning deficits.