Atomically precise photothermal nanomachines.

Interfacing molecular machines to inorganic nanoparticles can, in principle, lead to hybrid nanomachines with extended functions. Here we demonstrate a ligand engineering approach to develop atomically precise hybrid nanomachines by interfacing gold nanoclusters with tetraphenylethylene molecular rotors. When gold nanoclusters are irradiated with near-infrared light, the rotation of surface-decorated tetraphenylethylene moieties actively dissipates the absorbed energy to sustain the photothermal nanomachine with an intact structure and steady efficiency. Solid-state nuclear magnetic resonance and femtosecond transient absorption spectroscopy reveal that the photogenerated hot electrons are rapidly cooled down within picoseconds via electron-phonon coupling in the nanomachine. We find that the nanomachine remains structurally and functionally intact in mammalian cells and in vivo. A single dose of near-infrared irradiation can effectively ablate tumours without recurrence in tumour-bearing mice, which shows promise in the development of nanomachine-based theranostics.

Poly-Adenine-Based Spherical Nucleic Acids for Efficient Live-Cell MicroRNA Capture.

Direct delivery of exogenous non-coding nucleic acids into living cells has attracted intense interest in biological applications. However, the cell entry efficiency and target capture ability remain to be improved. Herein, we report a method for compartmenting the nucleic acids on the surface of poly-adenine-based spherical nucleic acids (polyA-SNAs) for efficient capture of oncogenic microRNAs (miRNAs) in living cells. We find that polyA-SNAs exhibit high cell entry efficiency, which is insensitive to the configuration of the anti-miRNA sequences. By programming the length of polyAs, we precisely engineered the spatial configuration of the anti-miRNA sequences in polyA-SNAs. Compartmentalized polyA-SNAs bind to miRNAs with improved capture ability as compared to densely compacted SNAs. We further demonstrate that polyA-SNAs serve as high-efficacy miRNA sponges for capturing oncogenic miRNAs both in living cells and in mice. The efficient inhibition of miRNAs results in significant suppression of tumor growth.

Hydrogen Sulfide-Activatable Second Near-Infrared Fluorescent Nanoassemblies for Targeted Photothermal Cancer Therapy.

Near-infrared (NIR)-II fluorescence agents hold great promise for deep-tissue photothermal therapy (PTT) of cancers, which nevertheless remains restricted by the inherent nonspecificity and toxicity of PTT. In response to this challenge, we herein develop a hydrogen sulfide (H2S)-activatable nanostructured photothermal agent (Nano-PT) for site-specific NIR-II fluorescence-guided PTT of colorectal cancer (CRC). Our in vivo studies reveal that this theranostic Nano-PT probe is specifically activated in H2S-rich CRC tissues, whereas it is nonfunctional in normal tissues. Activation of Nano-PT not only emits NIR-II fluorescence with deeper tissue penetration ability than conventional fluorescent probes but also generates high NIR absorption resulting in efficient photothermal conversion under NIR laser irradiation. Importantly, we establish NIR-II imaging-guided PTT of CRC by applying the Nano-PT agent in tumor-bearing mice, which results in complete tumor regression with minimal nonspecific damages. Our studies thus shed light on the development of cancer biomarker-activated PTT for precision medicine.

Imaging of Colorectal Cancers Using Activatable Nanoprobes with Second Near-Infrared Window Emission.

Fluorescent probes in the second near-infrared window (NIR-II) allow high-resolution bioimaging with deep-tissue penetration. However, existing NIR-II materials often have poor signal-to-background ratios because of the lack of target specificity. Herein, an activatable NIR-II nanoprobe for visualizing colorectal cancers was devised. This designed probe displays H2 S-activated ratiometric fluorescence and light-up NIR-II emission at 900-1300 nm. By using this activatable and target specific probe for deep-tissue imaging of H2 S-rich colon cancer cells, accurate identification of colorectal tumors in animal models were performed. It is anticipated that the development of activatable NIR-II probes will find widespread applications in biological and clinical systems.

Visualization of the hepatic and renal cell uptake and trafficking of tetrahedral DNA origami in tumour.

DNA nanostructures, known for their programmability, ease of modification, and favourable biocompatibility, have gained widespread application in the biomedical field. Among them, Tetrahedral DNA Origami (TDOs), as a novel DNA nanostructure, possesses well-defined structures, multiple modification sites, and large cavities, making it a promising drug carrier. However, current understanding of TDOs' interactions with biological systems, particularly with target cells and organs, remains unexplored, limiting its further applications in biomedicine. In this work, we prepared TDOs with an average particle size of 40 nm and labelled them with Cy5 fluorescent molecules. Following intravenous injection in mice, the uptake of TDOs by different types of liver and kidney cells was observed. Results indicated that TDOs accumulate in renal tubules and are metabolized by Kupffer cells, epithelial cells, and hepatocytes in the liver. Additionally, in a tumour-bearing mouse model, TDOs passively targeted tumour tissues and exhibited excellent tumour penetration and retention after rapid metabolism in hepatocytes. Our findings provide crucial insights for the development of TDO-based drug delivery systems.

Noninvasive Framework Nucleic Acid Eye Drops for Retinal Administration.

Intravitreal injection is widely employed for the treatment of retinal diseases. However, it suffers from various drawbacks, including ocular trauma, risk of infection, and poor patient compliance due to frequent administrations. Due to the presence of barriers such as the cornea, it has been a challenge to develop efficient noninvasive ophthalmic eye drops that can reach the retina. Framework nucleic acids (FNAs), known for their excellent biocompatibility and precise, controllable shape and size, have been extensively utilized in drug delivery application. Here, we report the development of size- and shape-resolved fluorescent DNA frameworks for noninvasive retinal administration. Results show that tetrahedral DNA nanostructures (TDNs) with an edge length of 20 bp can reach the retina within 6 h with the highest efficiency. Moreover, this delivery method exhibits excellent biocompatibility. Our findings provide an approach for the development of localized treatment strategies for retinal diseases using FNA-based nanocarriers.

DNA Framework Programmed Conformational Reconstruction of Antibody Complementary Determining Region.

The conformation of complementary determining region (CDR) is crucial in dictating its specificity and affinity for binding with an antigen, making it a focal point in artificial antibody engineering. Although desirable, programmable scaffolds that can regulate the conformation of individual CDRs with nanometer precision are still lacking. Here, we devise a strategy to program the CDR conformation by anchoring both ends of a free CDR loop to specific sites of a DNA framework structure. This method allows us to define the span of a single CDR loop with an ∼2 nm resolution. Using this approach, we create a series of DNA framework based artificial antibodies (DNFbodies) with varied CDR loop spans, leading to different antibody-antigen binding affinities. We find that an optimized single CDR loop (∼2.3 nm span) exhibits ∼3-fold improved affinity relative to natural antibodies, confirming the critical role of the CDR conformation. This study may inspire the rational design of artificial antibodies.

Inhibition of Bacteria In Vitro and In Vivo by Self-Assembled DNA-Silver Nanocluster Structures.

Antimicrobial nanomaterials hold great promise for bacteria-infected wound healing. However, it remains a challenge to balance antimicrobial efficacy and biocompatibility for these artificial antimicrobials. Here we employed biocompatible genetic molecule DNA as a building material to fabricate antimicrobial materials, including self-assembled Y-shaped DNA-silver nanocluster composite (Y-Ag) and Y-Ag hydrogel (Y-Ag-gel). We demonstrate that macroscopic and microcosmic DNA-Ag composites can effectively inhibit bacterial growth but do not affect cell proliferation in vitro. In particular, Y-Ag spray can speed up the process of wound healing in vivo. Considering the efficacy and advantages of DNA-based materials, our findings provide a promising route to fabricate a novel wound dressing such as spray and hydrogel for therapeutic wound healing.

Ultra-wide bandgap semiconductor Ga2O3 power diodes.

Ultra-wide bandgap semiconductor Ga2O3 based electronic devices are expected to perform beyond wide bandgap counterparts GaN and SiC. However, the reported power figure-of-merit hardly can exceed, which is far below the projected Ga2O3 material limit. Major obstacles are high breakdown voltage requires low doping material and PN junction termination, contradicting with low specific on-resistance and simultaneous achieving of n- and p-type doping, respectively. In this work, we demonstrate that Ga2O3 heterojunction PN diodes can overcome above challenges. By implementing the holes injection in the Ga2O3, bipolar transport can induce conductivity modulation and low resistance in a low doping Ga2O3 material. Therefore, breakdown voltage of 8.32 kV, specific on-resistance of 5.24 mΩ⋅cm2, power figure-of-merit of 13.2 GW/cm2, and turn-on voltage of 1.8 V are achieved. The power figure-of-merit value surpasses the 1-D unipolar limit of GaN and SiC. Those Ga2O3 power diodes demonstrate their great potential for next-generation power electronics applications.

Nanoenabled Tumor Oxygenation Strategies for Overcoming Hypoxia-Associated Immunosuppression.

Cancer immunotherapy, which initiates or strengthens innate immune responses to attack cancer cells, has shown great promise in cancer treatment. However, low immune response impacted by immunosuppressive tumor microenvironment (TME) remains a key challenge, which has been found related to tumor hypoxia. Recently, nanomaterial systems are proving to be excellent platforms for tumor oxygenation, which can reverse hypoxia-associated immunosuppression, strengthen the systemic antitumor immune responses, and thus afford a striking abscopal effect to clear metastatic cancer cells. In this review, we would like to survey recent progress in utilizing nanomaterials for tumor oxygenation through approaches such as in situ O2 generation, O2 delivery, tumor vasculature normalization, and mitochondrial-respiration inhibition. Their effects on tumor hypoxia-associated immunosuppression are highlighted. We also discuss the ongoing challenges and how to further improve the clinical prospect of cancer immunotherapy.

Genetically encoded X-ray cellular imaging for nanoscale protein localization.

Spatial resolution defines the physical limit of microscopes for probing biomolecular localization and interactions in cells. Whereas synchrotron-based X-ray microscopy (XRM) represents a unique approach for imaging a whole cell with nanoscale resolution due to its intrinsic nanoscale resolution and great penetration ability, existing approaches to label biomolecules rely on the use of exogenous tags that are multi-step and error-prone. Here, we repurpose engineered peroxidases as genetically encoded X-ray-sensitive tags (GXET) for site-specific labeling of protein-of-interest in mammalian cells. We find that 3,3'-diaminobenzidine (DAB) polymers that are in-situ catalytically formed by fusion-expressed peroxidases are visible under XRM. Using this new tag, we imaged the protein location associated with the alteration of a DNA-methylation pathway with an ultra-high resolution of 30 nanometers. Importantly, the excellent energy resolution of XRM enables multicolor imaging using different peroxidase tags. The development of GXET enlightens the way to nanoscopic imaging for biological studies.

Nanodiamond autophagy inhibitor allosterically improves the arsenical-based therapy of solid tumors.

Arsenic trioxide (ATO) is a successful chemotherapeutic drug for blood cancers via selective induction of apoptosis; however its efficacy in solid tumors is limited. Here we repurpose nanodiamonds (NDs) as a safe and potent autophagic inhibitor to allosterically improve the therapeutic efficacy of ATO-based treatment in solid tumors. We find that NDs and ATO are physically separate and functionally target different cellular pathways (autophagy vs. apoptosis); whereas their metabolic coupling in human liver carcinoma cells remarkably enhances programmed cell death. Combination therapy in liver tumor mice model results in ~91% carcinoma decrease as compared with ~28% without NDs. Treated mice show 100% survival rate in 150 days with greatly reduced advanced liver carcinoma-associated symptoms, and ~80% of post-therapy mice survive for over 20 weeks. Our work presents a novel strategy to harness the power of nanoparticles to broaden the scope of ATO-based therapy and more generally to fight solid tumors.

Serum protein corona-responsive autophagy tuning in cells.

Autophagy represents an important cellular response to nanoparticles (NPs), whose modulation holds great promise for developing nanomedicine. Here, we systematically studied cell autophagy responses elicited by the NP-protein corona with diverse protein corona types surrounding NPs with different sizes, shapes, and compositions. We demonstrated that these physicochemical properties of NP-protein coronas exerted a remarkable influence on cell autophagy responses. Particularly, for surface protein type-associated modulation of cell autophagy, we correlated the autophagy level to adsorbed protein type on Fe3O4 NPs. Accordingly, we could modulate cell autophagy in response to various levels of protein adsorption. Our work provides new clues to modulate cell autophagy by rational designing NP-protein complexes, which could aid in further biological and therapeutic applications.