Gas-involving cancer theranostics have attracted considerable attention in recent years due to their high therapeutic efficacy and biosafety. We have reviewed the recent significant advances in the development of stimuliresponsive gas releasing molecules (GRMs) and gas nanogenerators for cancer bioimaging, targeted and controlled gas therapy, and gas-sensitized synergistic therapy. We have focused on gases with known anticancer effects, such as oxygen (O 2 ), carbon monoxide (CO), nitric oxide (NO), hydrogen sulfide (H 2 S), hydrogen (H 2 ), sulfur dioxide (SO 2 ), carbon dioxide (CO 2 ), and heavy gases that act via the gas-generating process. The GRMs and gas nanogenerators for each gas have been described in terms of the stimulation method, followed by their applications in ultrasound and multimodal imaging, and finally their primary and synergistic actions with other cancer therapeutic modalities. The current challenges and future possibilities of gas therapy and imaging vis-a-vis clinical translation have also been discussed.

Recent reports have shown that intracellular, (super)paramagnetic ferritin nanoparticles can gate TRPV1, a non-selective cation channel, in a magnetic field. Here, we report the effects of differing field strength and frequency as well as chemical inhibitors on channel gating using a Ca 2+-sensitive promoter to express a secreted embryonic alkaline phosphatase (SEAP) reporter. Exposure of TRPV1ferritin-expressing HEK-293T cells at 30 °C to an alternating magnetic field of 501 kHz and 27.1 mT significantly increased SEAP secretion by ~ 82% relative to control cells, with lesser effects at other field strengths and frequencies. Between 30-32 °C, SEAP production was strongly potentiated 3.3-fold by the addition of the TRPV1 agonist capsaicin. This potentiation was eliminated by the competitive antagonist AMG-21629, the NADPH oxidase assembly inhibitor apocynin, and the reactive oxygen species (RoS) scavenger N-acetylcysteine, suggesting that ROS contributes to magnetogenetic TRPV1 activation. These results provide a rational basis to address the heretofore unknown mechanism of magnetogenetics. New approaches have been advanced for controlling signal transduction 1 , cell activity, and protein expression 2 with temporal precision, contributing to advances in on-demand biomanufacturing of protein biologics 3 , developing new tools for drug discovery 4 , in vitro expansion and differentiation of stem cells for regenerative medicine 5 , and regulating the activity of neurons and other cell types in vivo 5. One example is optogenetics, which uses precise wavelengths of light to stimulate light sensitive channels 6,7. Alternatively, gold nanorods (AuNRs) can be actuated by near-infrared (NIR) wavelengths to confer light-sensitivity to light-insensitive, heat-sensitive targets. Specifically, antibody-coated AuNRs targeted to transient receptor potential (TRP) vanilloid 1 (TRPV1) cation channels and integrins generated plasmonic heating when stimulated with select wavelengths of NIR light and gated Ca 2+ flux into cells to control cellular functions 8. In each optical technique, the low penetration depth of visible and NIR light into cellular systems limits application either in vitro or in vivo 9. Another example is chemogenetics, in which drug ligands can gate mutated ion channels 10 or G-protein coupled receptors 11. Chemogenetics does not require an implant but is limited by a slow onset of action that is dictated by the pharmacokinetics of the drug actuator in vivo and the addition of a chemical inducer to in vitro cell-based reactors 12. Still other approaches for activating signal transduction have been developed including the use of size-controlled microbubbles targeted to Piezo1 ion channels to gate Ca 2+ flux by ultrasound stimulation 13 and magnetic activation of engineered ion channels 14-18. The use of magnetic fields to gate TRPV1 and related ion channels has been shown in multiple studies. Pralle and co-workers used megahertz radio frequency (RF) alternating magnetic fields (AMFs) to gate TRPV1 when external ...

Excessive production of oxidative species alters the normal redox balance and leads to diseases,s uch as chronic inflammation and cancer.O xidative species are short-lived species,w hich makes direct, precise,a nd real-time measurements difficult. Herein, we report an ovel core-satellite gold nanostructure for dual, ratiometric surface-enhanced Raman scattering (SERS) and photoacoustic (PA) imaging to enable the precise detection of inflammation/cancer-related H 2 O 2 .The combination of H 2 O 2-activated second near-infrared (NIR-II) PA imaging and SERS imaging enables the differentiation between the inflamed region and normal tissue with high accuracy.The mesoporous silica shell of the nanoprobe could be used to deliver drugs to the target area to precisely treat disease.T herefore,t his core-satellite nanostructure can not only quantitatively and precisely monitor H 2 O 2 produced in inflammation, tumor,and osteoarthritis in rabbits in real-time, but can also be used to track the progress of the antiinflammatory treatment in real-time.

We developed dual biologically responsive nanogapped gold nanoparticle vesicles loaded with immune inhibitor and carrying an anticancer polymeric prodrug for synergistic concurrent chemo-immunotherapy against primary and metastatic tumors, along with guided cargo release by photoacoustic (PA) imaging in the second near-infrared (NIR-II) window. The responsive vesicle was prepared by self-assembly of nanogapped gold nanoparticles (AuNNPs) grafted with poly­(ethylene glycol) (PEG) and dual pH/GSH-responsive polyprodug poly­(SN38-co-4-vinylpyridine) (termed AuNNP@PEG/PSN38VP), showing intense PA signal in the NIR-II window. The effect of the rigidity of hydrophobic polymer PSN38VP on the assembled structures and the formation mechanism of AuNNP@SN38 Ve were elucidated by computational simulations. The immune inhibitor BLZ-945 was encapsulated into the vesicles, resulting in pH-responsive release of BLZ-945 for targeted immunotherapy, followed by the dissociation of the vesicles into single AuNNP@PEG/PSN38VP. The hydrophilic AuNNP@PEG/PSN38VP nanoparticles could penetrate deep into the tumor tissues and release the anticancer drug SN38 under the reductive environment. A PA signal in the NIR-II window in the deep tumor region was obtained. The BLZ-945-loaded vesicle enabled enhanced PA imaging-guided concurrent chemo-immunotherapy efficacy, inhibiting the growth of both primary tumors and metastatic tumors.

Detection of glutathione (GSH) in the body is essential to accurately map the redox state of cells and real‐time visualization of physiological and pathological conditions in vivo. However, traditional fluorescence (FL) imaging in the near‐infrared I region (NIR‐I, 650–900 nm) is difficult to quantitively visualize GSH in vivo due to the tissue autofluorescence background and disastrous photon scattering. Herein, a NIR‐IIb (1500–1700 nm) nanoprobe consisting of 4‐nitrophenol‐Cy7 (NPh) conjugated lanthanide‐based downconversion nanoparticles (DCNP@NPh‐PEG) is developed for in vivo ratiometric imaging of GSH. In the presence of GSH, NPh shows responsively enhanced FL emission at 808 nm, thus enhancing FL signal at 1550 nm of DCNPs excited by 808 nm (F1550, 808Ex) through non‐radiative energy transfer (NRET) effect, while the fluorescence of DCNP at 1550 nm excited by 980 nm laser (F1550, 980Ex) is stable because no NRET occurred. The ratiometric F1550, 980Ex/F1550, 808Ex value exhibits a linearship with GSH concentration ranged from 0–24 mm with detection limit of 0.3 mm. The NIR‐IIb nanoprobe has excellent performance in detecting and imaging GSH in both subcutaneous tumor and orthotopic colon tumor in vivo with high accuracy and resolution. The design strategy of the ratiometric NIR‐II FL nanoprobe based on the activated FERT effect provides a reliable tool for the development of NIR‐II nanoprobes for accurate biosensing in vivo.