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The in vivo optical imaging of RNA biomarkers of inflammation is hindered by low signal-to-background ratios, owing to non-specific signal amplification in healthy tissues. Here we report the design and in vivo applicability, for the imaging of inflammation-associated messenger RNAs (mRNAs), of a molecular beacon bearing apurinic/apyrimidinic sites, whose amplification of fluorescence is triggered by human apurinic/apyrimidinic endonuclease 1 on translocation from the nucleus into the cytoplasm specifically in inflammatory cells. We assessed the sensitivity and tissue specificity of an engineered molecular beacon targeting interleukin-6 (IL-6) mRNA in live mice, by detecting acute inflammation in their paws and drug-induced inflammation in their livers. This enzymatic-amplification strategy may enable the specific and sensitive imaging of other disease-relevant RNAs in vivo.

Protease-triggered control of functional DNA has remained unachieved, leaving a significant gap in activatable DNA biotechnology. Herein, we report the design of a protease-activatable aptamer system that can perform molecular sensing and imaging in a tumor-specific manner. The system is constructed by locking the structure-switching activity of an aptamer using a rationally designed PNA-peptide-PNA triblock copolymer. Highly selective protease-mediated cleavage of the peptide substrate results in reduced binding affinity of PNA to the aptamer module, with the subsequent recovery of its biosensing function. We demonstrated that the DNA/peptide/PNA hybrid system allows for tumor cell-selective ATP imaging in vitro and also produces a fluorescent signal in vivo with improved tumor specificity. This work illustrates the potential of bridging the gap between functional DNA and peptides for precise biomedical applications.

Despite progress on DNA-assembled nanoparticle (NP) superstructures, their complicated synthesis procedures hamper their potential biomedical applications. Here, we present an exceptionally simple strategy for the synthesis of single-stranded DNA (ssDNA) assembled Fe3O4 supraparticles (DFe-SPs) as magnetic resonance contrast agents. Unlike traditional approaches that assemble DNA-conjugated NPs via Watson-Crick hybridization, our DFe-SPs are formed with a high yield through one-step synthesis and assembly of ultrasmall Fe3O4 NPs via ssDNA-metal coordination bridges. We demonstrate that the DFe-SPs can efficiently accumulate into tumors for sensitive MR imaging. By virtue of reversible DNA-metal coordination bridges, the DFe-SPs could be disassembled into isolated small NPs in vivo, facilitating their elimination from the body. This work opens a new avenue for the ssDNA-mediated synthesis of superstructures, which expands the repertoire of DNA-directed NP assembly for biomedical applications.

DNA-based biosensor technologies have shown great potential in chemical and biological detection. These biosensors have been actively developed as probes for molecular imaging in live cells and in animals, allowing in situ detection of analytes in complex biological systems, elucidation of the roles of key molecules in biological processes, and the development of non-invasive diagnosis and image-guided surgery. Despite the progress made, improving the spatial-temporal precision remains a challenge in this field. In this Minireview, we describe the concepts behind spatiotemporally selective molecular imaging via the combination of engineered, light-activatable DNA-based biosensors and upconversion nanotechnology. We then highlight the application of the approach for the spatiotemporally controlled imaging of various targets in specific intracellular organelles, signal amplification, as well as the regulation of targeting activity to receptor proteins. We finally discuss the challenges and perspectives for possible future developments in this emerging field.

Despite the increasing usage of porphyrinic metal-organic frameworks (MOFs) for combination therapy, the controlled encapsulation of inorganic nanoparticle-based therapeutics into such MOFs with specific structures has remained a major obstacle for improved tumor therapy. Here, we report the synthesis of a mesoporous MOF shell on the surface of gold nanorods (AuNRs), wherein a single AuNR is captured individually in single-crystalline MOFs with a controlled crystallographic orientation, for combinational phototherapy against solid tumors. The core-shell heterostructures have the benefits of a mesoporous structure and photoinduced singlet oxygen generation behavior characterized by the porphyrinic MOF shell, together with the plasmonic photothermal conversion characteristic of AuNRs. We demonstrated that the AuNR@MOF nanoplatform enables an efficient tumor treatment strategy by combining photodynamic therapy and photothermal therapy. We should emphasize that such systems could have applications beyond the field of cancer therapy, like plasmonic harvesting of light energy to induce and accelerate catalytic reactions within MOFs and multifunctional nanocarriers for agricultural formulations.

DNA biotechnology offers intriguing opportunities for amplification-based sensitive detection. However, spatiotemporally-controlled manipulation of signal amplification for in situ imaging of the tumor microenvironment remains an outstanding challenge. Here, we demonstrate a DNA-based strategy that can spatial-selectively amplify the acidic signal in the extracellular milieu of the tumor to achieve specific imaging with improved sensitivity. The strategy, termed mild acidosis-targeted amplification (MAT-amp), leverages the specific acidic microenvironment to engineer tumor cells with artificial DNA receptors through a pH (low) insertion peptide, which permits controlled recruitment of fluorescent amplifiers via a hybridization chain reaction. The acidosis-responsive amplification cascade enables significant fluorescence enhancement in tumors with a reduced background signal in normal tissues, leading to improved signal-to-background ratio. These results highlight the utility of MAT-amp for in situ imaging of the microenvironment characterized by pH disequilibrium.

Metal-organic frameworks (MOFs) have shown great potential as nanophotosensitizers (nPSs) for photodynamic therapy (PDT). The use of such MOFs in PDT, however, is limited by the shallow depth of tissue penetration of short-wavelength light and the oxygen-dependent mechanism that renders it inadequate for hypoxic tumors. Here, to combat such limitations, we rationally designed core-shell upconversion nanoparticle@porphyrinic MOFs (UCSs) for combinational therapy against hypoxic tumors. The UCSs were synthesized in high yield through the conditional surface engineering of UCNPs and subsequent seed-mediated growth strategy. The heterostructure allows efficient energy transfer from the UCNP core to the MOF shell, which enables the near-infrared (NIR) light-triggered production of cytotoxic reactive oxygen species. A hypoxia-activated prodrug tirapazamine (TPZ) was encapsulated in nanopores of the MOF shell of the heterostructures to yield the final construct TPZ/UCSs. We demonstrated that TPZ/UCSs represent a promising system for achieving improved cancer treatment in vitro and in vivo via the combination of NIR light-induced PDT and hypoxia-activated chemotherapy. Furthermore, the integration of the nanoplatform with antiprogrammed death-ligand 1 (α-PD-L1) treatment promotes the abscopal effect to completely inhibit the growth of untreated distant tumors by generating specific tumor infiltration of cytotoxic T cells. Collectively, this work highlights a robust nanoplatform for combining NIR light-triggered PDT and hypoxia-activated chemotherapy with immunotherapy to combat the current limitations of tumor treatment.

Despite a growing interest in DNA nanomaterials, their simple synthesis remains a challenge. A simple and general strategy for constructing DNA-based nanomaterials by metal ion coordination is reported. The metal-DNA nanoparticles(NPs) could be synthesized with DNA molecules of diverse sequence and various metal ions of intrinsic property, resulting in multifunctional NPs with the combined advantages of both inorganic and DNA building blocks. It is demonstrated that the hybrid metal-DNA NPs could be engineered for magnetic resonance and luminescence imaging, encapsulation of multifarious nucleic acids with controlled ratio, and co-assembly with small drug molecules. Furthermore, because these metal-DNA NPs exhibited enhanced cellular uptake compared to free synthetic DNA, they hold potential for applications in diagnostics and therapeutics.

Immunomodulatory therapies are becoming a paradigm-shifting treatment modality for cancer. Despite promising clinical results, cancer immunotherapy is accompanied with off-tumor toxicity and autoimmune adverse effects. Thus, the development of smarter systems to regulate immune responses with superior spatiotemporal precision and enhanced safety is urgently needed. Here we report an activatable engineered immunodevice that enables remote control over the antitumor immunity in vitro and in vivo with near-infrared (NIR) light. The immunodevice is composed of a rationally designed UV light-activatable immunostimulatory agent and upconversion nanoparticle, which acts as a transducer to shift the light sensitivity of the device to the NIR window. The controlled immune regulation allows the generation of effective immune response within tumor without disturbing immunity elsewhere in the body, thereby maintaining the antitumor efficacy while mitigating systemic toxicity. The present work illustrates the potential of the remote-controlled immunodevice for triggering of immunoactivity at the right time and site., The use of immunotherapy can be limited by adverse side effects. In this study, the authors designed a nanodevice that spatiotemporally controlled activate immunomodulatory agents at the tumour site upon near-infrared light triggering, thus preventing systemic toxicity with maintained efficacy

superstructures has enormous potential in material sciences and engineering. Despite the potential, controlled assembly of different kinds of NPs into spatially addressable hybrid configurations still remains a formidable challenge. Herein, we report a simple and universal strategy for DNA-mediated assembly of CdTe quantum dots (QDs) and lanthanide-doped upconversion nanoparticles (UCNPs). Such DNA-QD/UCNPs heterostructures not only maintains both fluorescent properties of QDs and upconversion luminescence behaviors of UCNPs, but also offers a polyvalent DNA surface, allowing for targeted dual-modality imaging of cancer cells using an aptamer. The hetero-assembly mediated by the DNA − inorganic interfacial interaction may provide a scalable way to fabricate hybrid superstructures of both theoretical and practical interests.

Orthogonal near-infrared light–controlled DNA nanodevices allow for biorecognition and treatment at right time and place., Despite the potential of nanodevices for intelligent drug delivery, it remains challenging to develop controllable therapeutic devices with high spatial-temporal selectivity. Here, we report a DNA nanodevice that can achieve tumor recognition and treatment with improved spatiotemporal precision under the regulation of orthogonal near-infrared (NIR) light. The nanodevice is built by combining an ultraviolet (UV) light–activatable aptamer module and a photosensitizer (PS) with up-conversion nanoparticle (UCNP) that enables the operation of the nanodevice with deep tissue–penetrable NIR light. The UCNPs can convert two distinct NIR excitations into orthogonal UV and green emissions for programmable photoactivation of the aptamer modules and PSs, respectively, allowing spatiotemporally controlled target recognition and photodynamic antitumor effect. Furthermore, when combined with immune checkpoint blockade therapy, the nanodevice results in regression of untreated distant tumors. This work provides a new approach for regulation of diagnostic and therapeutic activity at the right time and place.

Designer DNA nanodevices have attracted extensive interest for detection of specific targets in living cells. However, it still remains a great challenge to construct DNA sensing devices that can be activated at desired time with a remotely applied stimulus. Here we report a rationally designed, synthetic DNA nanodevice that can detect ATP in living cells in an upconversion luminescence-activatable manner. The nanodevice consists of a UV light-activatable aptamer probe and lanthanide-doped upconversion nanoparticles which acts as the nanotransducers to operate the device in response to NIR light. We demonstrate that the nanodevice not only enables efficient cellular delivery of the aptamer probe into live cells, but also allows the temporal control over its fluorescent sensing activity for ATP by NIR light irradiation in vitro and in vivo. Ultimately, with the availability of diverse aptamers selected in vitro, the DNA nanodevice platform will allow NIR-triggered sensing of various targets as well as modulation of biological functions in living systems.

Here we report, for the first time, the growth of single-crystalline mesoporous MOFs with well-controlled orientation on the surface of gold nanorods. Importantly, it showed that trace amounts of water could induce the formation of MOFs of different phases and shapes, which was critical for the synthesis of such mesoporous heterostructures.

Creating nanoparticle dimers has attracted extensive interest. However, it still remains a great challenge to synthesize heterodimers with asymmetric compositions and synergistically enhanced functions. In this work, we report the synthesis of high quality heterodimers composed of porphyrinic nanoscale metal-organic frameworks (nMOF) and lanthanide-doped upconversion nanoparticles (UCNPs). Due to the dual optical properties inherited from individual nanoparticles and their interactions, absorption of low energy photons by the UCNPs is followed by energy transfer to the nMOFs, which then undergo activation of porphyrins to generate singlet oxygen. Furthermore, the strategy enables the synthesis of heterodimers with tunable UCNP size and dual NIR light harvesting functionality. We demonstrated that the hybrid architectures represent a promising platform to combine NIR-induced photodynamic therapy and chemotherapy for efficient cancer treatment. We believe that such heterodimers are capable of expanding their potential for applications in solar cells, photocatalysis, and nanomedicine.

Herein, we report the design and synthesis of a mitochondria-specific, 808 nm NIR light-activated photodynamic therapy (PDT) system based on the combination of metal-organic frameworks (MOFs) and upconversion photochemistry with an organelle-targeting strategy. The system was synthesized through the growth of a porphyrinic MOF on Nd

There is intense interest in intracellular co-delivery of functional proteins and nucleic acids for diverse biological research and disease treatment. However, efficient co-encapsulation of these two types of biomacromolecules within a single particle remains an outstanding challenge because of their significantly different characteristics and loading competition inside the particles. Here we report an extremely simple approach to produce a hybrid platform for the co-delivery of proteins and nucleic acids into cancer cells. This system was constructed by one-step, coordination-driven self-assembly of proteins and nucleic acids with metal ions, resulting in spherical hybrid architectures with uniform size, ultrahigh loading content and tunable ratios of the two macromolecular components. The platform enables efficient co-delivery of protein and nucleic acid therapeutics into cells and achieves a significant inhibition of tumor growth in vivo. The simple self-assembly strategy offers an effective tool for the co-delivery of macromolecular therapeutics and has great potential for personalized medicine.

Developing simple and general approaches for the synthesis of nanometer-sized DNA materials with specific morphologies and functionalities is important for various applications. Herein, a novel approach for the synthesis of a new set of DNA-based nanoarchitectures through coordination-driven self-assembly of FeII ions and DNA molecules is reported. By fine-tuning the assembly, Fe-DNA nanospheres of precise sizes and controlled compositions can be produced. The hybrid nanoparticles can be tailored for delivery of functional DNA to cells in vitro and in vivo with enhanced biological function. This highlights the potential of metal ion coordination as a tool for directing the assembly of DNA architectures, which conceptualizes a new pathway to expand the repertoire of DNA-based nanomaterials. This methodology will advance both the fields of DNA nanobiotechnology and metal-ligand coordination chemistry.

Surface functionality is an essential component for processing and application of metal-organic frameworks (MOFs). A simple and cost-effective strategy for DNA-mediated surface engineering of zirconium-based nanoscale MOFs (NMOFs) is presented, capable of endowing them with specific molecular recognition properties and thus expanding their potential for applications in nanotechnology and biotechnology. It is shown that efficient immobilization of functional DNA on NMOFs can be achieved via surface coordination chemistry. With this strategy, it is demonstrated that such porphyrin-based NMOFs can be modified with a DNA aptamer for targeting specific cancer cells. Furthermore, the DNA-NMOFs can facilitate the delivery of therapeutic DNA (e.g., CpG) into cells for efficient recognition of endosomal Toll-like receptor 9 and subsequent enhanced immunostimulatory activity in vitro and in vivo. No apparent toxicity is observed with systemic delivery of the DNA-NMOFs in vivo. Overall, these results suggest that the strategy allows for surface functionalization of MOFs with different functional DNAs, extending the use of these materials to diverse applications in biosensor, bioimaging, and nanomedicine.

Extracellular ATP is an emerging target for cancer treatment because it is a key messenger for shaping the tumor microenvironment (TME) and regulating tumor progression. However, it remains a great challenge to design biochemical probes for targeted imaging of extracellular ATP in the TME. A TME-driven DNA nanomachine (Apt-LIP) that permits spatially controlled imaging of ATP in the extracellular milieu of tumors with ultrahigh signal-to-background ratio is reported. It operates in response to the mild acidity in the TME with the pH (low) insertion peptide (pHLIP) module, thus allowing the specific anchoring of the structure-switching signaling aptamer unit to the membrane of tumor cells for "off-on" fluorescence imaging of the extracellular ATP. Apt-LIP allows for acidity driven visualization of different extracellular concentrations of exogenous ATP, as well as the monitoring of endogenous ATP release from cells. Furthermore, it is demonstrated that Apt-LIP represents a promising platform for the specific imaging of the extracellular ATP in both primary and metastatic tumors. Ultimately, since diverse aptamers are obtained through in vitro selection, this design strategy can be further applied for precise detection of various extracellular targets in the TME.

Fluorescent nanoprobes are indispensable tools to monitor and analyze biological species and dynamic biochemical processes in cells and living bodies. Conventional nanoprobes have limitations in obtaining imaging signals with high precision and resolution because of the interference with biological autofluorescence, off-target effects, and lack of spatiotemporal control. As a newly developed paradigm, light-activated nanoprobes, whose imaging and sensing activity can be remotely regulated with light irradiation, show good potential to overcome these limitations. Herein, recent research progress on the design and construction of light-activated nanoprobes to improve bioimaging and sensing performance in complex biological systems is introduced. First, recent innovative strategies and their underlying mechanisms for light-controlled imaging are reviewed, including photoswitchable nanoprobes and phototargeted nanosystems. Subsequently, a short highlight is provided on the development of light-activatable nanoprobes for biosensing, which offer possibilities for the remote control of biorecognition and sensing activity in a precise manner both temporally and spatially. Finally, perspectives and challenges in light-activated nanoprobes are commented.