Anticancer drugs embedded in or conjugated with inert nanocarriers, referred to as nanomedicines, show many therapeutic advantages over free drugs, but the inert carrier materials are the major component (generally more than 90%) in nanomedicines, causing low drug loading contents and thus excessive uses of parenteral excipients. Herein, we demonstrate a new concept directly using drug molecules to fabricate nanocarriers in order to minimize use of inert materials, substantially increase the drug loading content, and suppress premature burst release. Taking advantage of the strong hydrophobicity of the anticancer drug camptothecin (CPT), one or two CPT molecule(s) were conjugated to a very short oligomer chain of ethylene glycol (OEG), forming amphiphilic phospholipid-mimicking prodrugs, OEG-CPT or OEG-DiCPT. The prodrugs formed stable liposome-like nanocapsules with a CPT loading content as high as 40 or 58 wt % with no burst release in aqueous solution. OEG-DiCPT released CPT once inside cells, which showed high in vitro and in vivo antitumor activity. Meanwhile, the resulting nanocapsules can be loaded with a water-soluble drug-doxorubicin salt (DOX.HCl)-with a high loading efficiency. The DOX.HCl-loaded nanocapsules simultaneously delivered two anticancer drugs, leading to a synergetic cytotoxicity to cancer cells. The concept directly using drugs as part of a carrier is applicable to fabricating other highly efficient nanocarriers with a substantially reduced use of inert carrier materials and increased drug loading content without premature burst release.

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.

Nanodevices have potential as intelligent sensing systems for detection of microRNAs (miRNAs) in living cells. However, the resolution offered by “always active” nanodevices is often insufficient to manipulate miRNA sensing with high spatiotemporal control. In this work, using DNA nanotechnology we constructed an activatable DNA nanodevice programmed to detect miRNAs in vitro and in vivo with the high spatial and temporal precision of NIR light. Our nanodevice is functionalized on the surface of upconversion nanoparticles (UCNPs) with a rationally designed DNA beacon that displays UV light-activatable miRNA sensing activity. The UCNPs absorb deep-tissue-penetrable NIR light and emit high-energy UV light locally, which serve as transducers to operate the nanodevice in the NIR window. The nanodevice can naturally enter cells and enable remote regulation of its fluorescent imaging activity for miRNAs in living cells by NIR light illumination in a chosen place and time. Furthermore, we demonstrate that the nanodevice can be expanded to activatable imaging of intratumoral miRNAs in living mice. This work illustrates the potential of DNA nanodevices for miRNA detection with high spatiotemporal resolution, which could expand the toolbox of technologies for precise biological and medical analysis.

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 Nd3+‐sensitized upconversion nanoparticles to achieve Janus nanostructures with further asymmetric functionalization of the surface of the MOF domain. The PDT nanoplatform allows for photosensitizing with 808 nm NIR light, which could effectively avoid the laser‐irradiation‐induced overheating effect. Furthermore, mitochondria‐targeting could amplify PDT efficacy through the depolarization of the mitochondrial membrane and the initiation of intrinsic apoptotic pathway. This work sheds light on the hybrid engineering of MOFs to combat their current limitations for PDT.

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.

Understanding of the functions of enzymes in diverse cellular processes is important, but the design of sensors with controllable localization for in situ imaging of subcellular levels of enzymatic activity is particularly challenging. We introduce herein as patiotemporally controlled sensor technology that permits in situ localization and photoactivated imaging of human apurinic/apyrimidinic endonuclease 1 (APE1) within an intracellular organelle of choice (e.g., mitochondria or nucleus). The hybrid sensor platform is constructed by photoactivatable engineering of aD NA-based fluorescent probe and further combination with an upconversion nanoparticle and as pecific organelle localization signal. Controlled localization and NIR-light-mediated photoactivation of the sensor "on demand" effectively constrains the imaging signal to the organelle of interest, with improved subcellular resolution. We further demonstrate the application of the nanosensors for the imaging of subcellular APE1 translocation in response to oxidative stress in live cells.

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.

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