Neuromodulation is crucial for the understanding of brain circuits and treatment of neurological diseases. This work demonstrates a new photoacoustic nanoparticlebased neural stimulation technique. Synthesized nanoparticles transduce nearinfrared light to ultrasound locally at the neuronal membrane and evoke neural activation in vitro and in vivo. Through targeting the mechanosensitive ion channel TRPV4, the modified nanotransducers achieve neural activation with enhanced specificity. Together, photoacoustic nanotransducers offer opportunities for nongenetic neuromodulation with deep tissue penetration.

Radiotherapy (RT) in practical use often suffers from offtarget side effects and ineffectiveness against hypoxic tumor microenvironment (TME) as well as remote metastases. With regard to these problems, herein, we provide semiconductor heterojunction structured WO 2.9 -WSe 2 -PEG nanoparticles to realize a synergistic RT/photothermal therapy (PTT)/checkpoint blockade immunotherapy (CBT) for enhanced antitumor and antimetastatic effect. Based on the heterojunction structured nanoparticle with high Z element, the nanosystem could realize non-oxygen-dependent reactive oxygen species generation by catalyzing highly expressed H 2 O 2 in TME upon X-ray irradiation, which could further induce immunogenic cell death. Meanwhile, this nanosystem could also induce hyperthermia upon near-infrared irradiation to enhance RT outcome. With the addition of anti-PD-L1 antibody-based CBT, our results give potent evidence that local RT/PTT upon mild temperature and low radiation dose could efficiently ablate local tumors and inhibit tumor metastasis as well as prevent tumor rechallenge. Our study provides not only one kind of radiosensitizer based on semiconductor nanoparticles but also a versatile nanoplatform for simultaneous triple-combined therapy (RT/PTT/CBT) for treating both local and metastasis tumors.

Neural interfaces using biocompatible scaffolds provide crucial properties for the functional repair of nerve injuries and neurodegenerative diseases, including cell adhesion, structural support, and mass transport. Neural stimulation has also been found to be effective in promoting neural regeneration. This work provides a new strategy to integrate photoacoustic (PA) neural stimulation into hydrogel scaffolds using a nanocomposite hydrogel approach. Specifically, polyethylene glycol (PEG)-functionalized carbon nanotubes (CNT), highly efficient photoacoustic agents, are 2 embedded into silk fibroin to form biocompatible and soft photoacoustic materials. We show that these photoacoustic functional scaffolds enable non-genetic activation of neurons with a spatial precision defined by the area of light illumination, promoting neuron regeneration. These CNT/silk scaffolds offered reliable and repeatable photoacoustic neural stimulation. 94% of photoacoustic stimulated neurons exhibit a fluorescence change larger than 10% in calcium imaging in the light illuminated area. The on-demand photoacoustic stimulation increased neurite outgrowth by 1.74fold in a dorsal root ganglion model, when compared to the unstimulated group. We also confirmed that photoacoustic neural stimulation promoted neurite outgrowth by impacting the brain-derived neurotrophic factor (BDNF) pathway. As a multifunctional neural scaffold, CNT/silk scaffolds demonstrated non-genetic PA neural stimulation functions and promoted neurite outgrowth, providing a new method for non-pharmacological neural regeneration.

Tumor hypoxia is known to be one of the vital factors that aggravate tumor resistance to radiation therapy (RT) in which oxygen plays a critical role in tumor destruction. Herein, we synthesize a simple nanoradiosensitizer based on ultrathin BiO2–x nanosheets (NSs) modified with Tween 20 (T-BiO2–x NSs) to overcome the hypoxia-induced radioresistance as well as increase the efficacy of RT. On the one hand, bismuth as a high-Z element can effectively enhance the sensitivity of RT by depositing a higher radiation dose in tumors. The semiconductor property also endows its photocatalytic ability to produce extra reactive oxygen species (ROS) by reaction with the surrounding water. On the other hand, the defect-abundant BiO2–x NSs are also found to decompose the highly expressed hydrogen peroxide (H2O2) at the tumor site into oxygen (O2) for combating hypoxia. Both in vitro and in vivo experiments indicate that the as-prepared T-BiO2–x NSs could effectively inhibit tumor growth with X-ray irradiation. Our work thus provides a simple nanoradiosensitizer with multifunctionalities for increasing the RT efficacy while alleviating tumor hypoxia at the same time.

Spectral computed tomography (CT) imaging as a novel imaging technique shows promising prospects in the accurate diagnosis of various diseases. However, clinically iodinated contrast agents suffer from poor signal-to-noise ratio, and emerging heavy-metal-based CT contrast agents arouse great biosafety concern. Herein, we show the fabrication of rhenium sulfide (ReS2) nanoparticles, a clinic radiotherapy sensitizer, as a biosafe spectral CT contrast agent for the gastrointestinal tract imaging and tumor theranostics in vivo by teaching old drugs new tricks. The ReS2 nanoparticles were fabricated in a one-pot facile method at room temperature, and exhibited sub-10 nm size, favorable monodispersity, admirable aqueous solubility, and strong X-ray attenuation capability. More importantly, the proposed nanoparticles possess an outstanding spectral CT imaging ability and undoubted biosafety as a clinic therapeutic agent. Besides, the ReS2 nanoparticles possess appealing photothermal performance due to their intense near-infrared absorption. The proposed nano-agent not only guarantees obvious contrast enhancement in gastrointestinal tract spectral CT imaging in vivo, but also allows effective CT imaging-guided tumor photothermal therapy. The proposed “teaching old drugs new tricks” strategy shortens the time and cuts the cost required for clinical application of nano-agents based on existing clinical toxicology testing and trial results, and lays down a low-cost, time-saving, and energy-saving method for the development of multifunctional nano-agents toward clinical applications.

High precision neuromodulation is a powerful tool to decipher neurocircuits and treat neurological diseases. Current non-invasive neuromodulation methods offer limited precision at the millimeter level. Here, we report optically-generated focused ultrasound (OFUS) for non-invasive brain stimulation with ultrahigh precision. OFUS is generated by a soft optoacoustic pad (SOAP) fabricated through embedding candle soot nanoparticles in a curved polydimethylsiloxane film. SOAP generates a transcranial ultrasound focus at 15 MHz with an ultrahigh lateral resolution of 83 µm, which is two orders of magnitude smaller than that of conventional transcranial-focused ultrasound (tFUS). Here, we show effective OFUS neurostimulation in vitro with a single ultrasound cycle. We demonstrate submillimeter transcranial stimulation of the mouse motor cortex in vivo. An acoustic energy of 0.6 mJ/cm2, four orders of magnitude less than that of tFUS, is sufficient for successful OFUS neurostimulation. OFUS offers new capabilities for neuroscience studies and disease treatments by delivering a focus with ultrahigh precision non-invasively.

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Photothermal therapy (PTT) with the advantages of high efficiency and minimal invasiveness is a promising technique for tumor therapy, but clinical application of PTT agents has been stifled by the great safety concerns. Herein, a deep blue iodine−starch−alginate (ALG) hydrogel is elegantly fabricated based on the classic and simple "iodine−starch test" for in vivo tumor PTT in a facile and mild way. The iodine−starch−ALG hydrogel composed of clinically used agents is fabricated by dispersing blue iodine−starch complex into alginate−Ca 2+ hydrogel, which guarantees the good chemical stability of iodine−starch complex via separating them from surrounding reductive environment. The iodine−starch−ALG hydrogel possesses favorable biocompatibility derived from the biosafe and degradable components and possesses good photothermal heating ability based on iodine−starch chromophore. The proposed iodine−starch−ALG hydrogel is successfully applied in tumor PTT in vitro and in vivo for the first time. This work lays down a novel way for the development of high-performance and biocompatible biomaterials via teaching old drugs new tricks.