In glucose-stimulated insulin secretion (GSIS) of pancreatic β-cells, the rise of free cytosolic Ca²⁺ concentration through voltage-gated calcium channels (VGCCs) triggers the exocytosis of insulin-containing granules. Recently, mechanically induced insulin secretion pathways were also reported, which utilize free cytosolic Ca²⁺ ions as a direct regulator of exocytosis. In this study, we aimed to investigate intracellular Ca²⁺ responses on the HIT-T15 pancreatic β-cell line upon low-intensity pulsed ultrasound (LIPUS) stimulation and found that ultrasound induces two distinct types of intracellular Ca²⁺ oscillation, fast-irregular and slow-periodic, from otherwise resting cells. Both Ca²⁺ patterns depend on the purinergic signaling activated by the rise of extracellular ATP or ADP concentration upon ultrasound stimulation, which facilitates the release through mechanosensitive hemichannels on the plasma membrane. Further study demonstrated that two subtypes of purinergic receptors, P₂X and P₂Y, are working in a competitive manner depending on the level of glucose in the cell media. The findings can serve as an essential groundwork providing an underlying mechanism for the development of a new therapeutic approach for diabetic conditions with further validation.

Cell-based cancer immunotherapy holds potential as a therapeutic approach, yet its application for solid tumour treatment remains challenging. Here we report a focused-ultrasound-based approach that mechanically induces the localized expression of CD19 antigen within a subpopulation of cells within solid tumours, which function as local ‘training centres’ to activate chimeric antigen receptor T cells. Activated chimeric antigen receptor T cells attack the whole cancer cell population near the tumour site, thus achieving cancer suppression. The system achieves targeted gene expression by integrating focused-ultrasound-triggered mechanical stimulation and the subsequent calcium response of cancer cells with a doxycycline-gated AND-logic genetic circuit, both of which need to be active for effective induction of CD19 expression. We validate the functionality of the approach in vitro, in organoids and in vivo, achieving direct control of user-designed gene expressions through FUS-mediated mechanical stimulation without the need of any cofactor, demonstrating the approach’s potential as a versatile platform for precisely controllable immunotherapy. Overall, our combinatorial approach offers a focused-ultrasound-controlled remote and non-invasive priming of solid tumours for effective and safe chimeric antigen receptor T cell immunotherapy via the induced production of clinically validated antigens.

Ultrasound can safely penetrate deep into biological tissues, which has allowed this modality to be extensively used in clinical applications including diagnostic imaging, thermal ablation and lithotripsy. Recent identification of ultrasound-sensitive molecular actuators has led to the development of sonogenetics, a new and rapidly growing field. Here, these actuators are expressed in target cells, sensitizing these cells to the mechanical and/or thermal bioeffects of ultrasound, allowing them to be selectively manipulated using non-invasive ultrasound stimulation with high spatial and temporal precision. In this review, we will outline current sonogenetic approaches to manipulate both neurons and immune cells in vitro and in vivo, along with some practical considerations associated with designing these studies. Additionally, we highlight some exciting ongoing avenues for research and provide perspectives on the future of sonogenetics in the lab and the clinic. We suggest that by combining cell type resolution with the non-invasive nature of ultrasound stimulation, sonogenetics has the potential to revolutionize both scientific research and clinical practice.

Focused ultrasound (FUS) is a rapidly developing stimulus technology with the potential to uncover novel mechanosensory dependent cellular processes. Since it is noninvasive, it holds great promise for future therapeutic applications in patients used either alone or as a complement to boost existing treatments. For example, FUS stimulation causes invasive but not noninvasive cancer cell lines to exhibit marked activation of calcium signaling pathways. Here, we identify the membrane channel PANNEXIN1 (PANX1) as a mediator for activation of calcium signaling in invasive cancer cells. Knockdown of PANX1 decreases calcium signaling in invasive cells, while PANX1 overexpression enhances calcium elevations in non-invasive cancer cells. We demonstrate that FUS may directly stimulate mechanosensory PANX1 localized in endoplasmic reticulum to evoke calcium release from internal stores. This process does not depend on mechanosensory stimulus transduction through an intact cytoskeleton and does not depend on plasma membrane localized PANX1. Plasma membrane localized PANX1 however plays a different role in mediating the spread of intercellular calcium waves via ATP release. Additionally, we show that FUS stimulation evokes cytokine/chemokine release from invasive cancer cells, suggesting that FUS could be an important new adjuvant treatment to improve cancer immunotherapy.

Ultrasound can penetrate centimetres of soft tissue, focus energy with millimetre precision, and operate safely under real-time image guidance. Leveraging these advantages, sonogenetics combines therapeutic ultrasound with genetic, cellular, and molecular engineering to create remotely programmable living systems. While widely applied in neuronal modulation, this review highlights recent progress in precision medicine, focusing on immunoengineering and genome engineering, illustrating how sonogenetics is moving beyond neuromodulation to enable precise control of immune responses and targeted genetic modifications. We introduce the fundamental principles of sonogenetics and key ultrasound-responsive biological actuators, including heat-shock promoters, thermosensitive and mechanosensitive ion channels, gas vesicles, microbubbles, and acoustically responsive nanoparticles. These convert acoustic signals into biological responses and are integrated into synthetic genetic circuits to control cell behaviour with high spatial and temporal precision. We then overview immunoengineering and genome engineering, covering cellular therapies such as CAR-T and engineered bacteria, synthetic materials, and CRISPR-based genome and transcriptome editors. This context supports recent applications, including ultrasound-guided immune modulation, remote control of CAR-T cells, tumour microenvironment reprogramming, targeted genome editing, and epigenetic regulation in vivo. We also discuss the emerging role of artificial intelligence in optimizing sonogenetic designs and outline translational challenges, including actuator safety and immunogenicity, ultrasound penetration limits, targeting accuracy, and regulatory pathways for device-biologic combinations. Key priorities include closed-loop dosimetry, scalable vector delivery, and actuator optimization. In summary, sonogenetics provides a programmable, non-invasive toolkit for controlling cellular functions, opening opportunities in basic research, diagnostics, and next-generation therapeutics.

CAR-T therapy is highly effective in hematologic malignancies but remains challenging in solid tumors. To address this challenge, here, we developed SHIFTERS (solid-tumor hallmark inducible, focused-ultrasound triggered enhanced reprogramming system), an AND-gated circuit that rewires tumor hallmarks into the clinically validated antigen CD19 under focused-ultrasound (FUS) control. SHIFTERS uses a split Gal4-VP64 transcription factor with one module driven by a hypoxia-responsive promoter and the other by a FUS-inducible heat-shock promoter, restricting CD19 induction to sonicated, hallmark-positive regions. This design enables robust, sustained local CD19 expression to activate and train CD19 synNotch CAR-T cells. In 3D spheroids and in vivo models, hypoxia-gated SHIFTERS combined with synNotch CAR-T cells achieved strong tumor suppression, supporting FUS-guided, localized activation. SHIFTERS is modular and can be adapted to tumor-type–specific promoters such as enAFP in hepatocellular carcinoma to enable both spatial and cell type–specific targeting. Together, SHIFTERS provides a modular, tumor-constrained, ultrasound-controllable platform to improve the precision and efficacy of CAR-T therapy for solid tumors.