Multiple drug resistance is a persistent obstacle for efficient chemotherapy of cancer. Herein, we report a novel drug delivery platform. A zeolitic imidazole framework-8 (ZIF-8) film with a few nanometer thickness was in situ synthesized on the surface of carboxylated mesoporous silica (MSN-COOH) nanoparticles (NPs) for pore blocking and efficient loading of small interfering RNAs to fabricate a pH-responsive drug delivery system. The ZIF-8 film could convert the charge of MSN-COOH from negative to positive for efficient loading of siRNA via electrostatic interactions and protect siRNA from nuclease degradation. The positively charged ZIF-8 film facilitates cellular uptake and endo-lysosome escape of the NPs. In addition, the ultrathin ZIF-8 film can decompose in the acidic endo-lysosome and trigger the intracellular release of siRNAs and chemotherapeutic drugs, leading to a significantly enhanced chemotherapeutic efficacy for multidrug-resistant cancer cells including MCF-7/ADR and SKOV-3/ADR cells as demonstrated by the confocal laser scanning microscopy image, cell viability assay, Annexin V&PI staining, and flow cytometry. This approach provides a promising strategy for pH-triggered, stimuli-responsive delivery of nucleic acid drugs and chemotherapeutic agents with remarkably enhanced chemotherapeutic efficacy.

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Monitoring spiking activity across large neuronal populations at behaviorally relevant timescales is critical for understanding neural circuit function. Unlike calcium imaging, voltage imaging requires kilohertz sampling rates which reduces fluorescence detection to near shot noise levels. High-photon flux excitation can overcome photon-limited shot noise but photo-bleaching and photo-damage restricts the number and duration of simultaneously imaged neurons. We investigated an alternative approach aimed at low two-photon flux, voltage imaging below the shot noise limit. This framework involved developing: a positive-going voltage indicator with improved spike detection (SpikeyGi); an ultra-fast two-photon microscope for kilohertz frame-rate imaging across a 0.4x0.4mm2 field of view, and; a self-supervised denoising algorithm (DeepVID) for inferring fluorescence from shot-noise limited signals. Through these combined advances, we achieved simultaneous high-speed, deep-tissue imaging of more than one hundred densely-labeled neurons over one hour in awake behaving mice. This demonstrates a scalable approach for voltage imaging across increasing neuronal populations.

Transcranial focused ultrasound (tFUS) is an emerging non-invasive brain stimulation tool for safely and reversibly modulating brain circuits. The effectiveness of tFUS on human brain has been demonstrated, but how tFUS influences the human voluntary motor processing in the brain remains unclear. Methods: We apply low-intensity tFUS to modulate the movement-related cortical potential (MRCP) originating from human subjects practicing a voluntary foot tapping task. 64channel electroencephalograph (EEG) is recorded concurrently and further used to reconstruct the brain source activity specifically at the primary leg motor cortical area using the electrophysiological source imaging (ESI). Results: The ESI illustrates the ultrasound modulated MRCP source dynamics with high spatiotemporal resolutions. The MRCP source is imaged and its source profile is further evaluated for assessing the tFUS neuromodulatory effects on the voluntary MRCP. Moreover, the effect of ultrasound pulse repetition frequency (UPRF) is further assessed in modulating the MRCP. The ESI results show that tFUS significantly increases the MRCP source profile amplitude (MSPA) comparing to a sham ultrasound condition, and further, a high UPRF enhances the MSPA more than a low UPRF does. Conclusion: The present results demonstrate the neuromodulatory effects of the low-intensity tFUS on enhancing the human voluntary movement-related cortical activities evidenced through the ESI imaging. Significance: This work provides the first evidence of tFUS enhancing the human endogenous motor cortical activities through excitatory modulation.

Cellular disease and senescence are often accompanied by an imbalance in the local oxygen supply.

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