N Nature Biotechnology · Nov 10, 2025 Clearance of intracranial debris by ultrasound reduces inflammation and improves outcomes in hemorrhagic stroke models Impaired clearance of neurotoxic debris in the brain exacerbates neurologic disease and presents a promising therapeutic target. Pharmacologic therapies can enhance meningeal lymphatic clearance in preclinical models but may be limited by systemic toxicities or invasive administration. Here we report a low-intensity, focused ultrasound protocol that noninvasively clears pathogenic substances from the cerebrospinal fluid and brain interstitium in mice. Using two models of hemorrhagic stroke, we demonstrate that this protocol clears the cerebrospinal fluid and interstitium of blood cells, which accumulate in the deep cervical lymph nodes via meningeal lymphatics. The protocol directly modulates molecular processes, including mechanosensitive channels, to shift microglial phenotypes and astrocytic aquaporin localization to reduce neuroinflammation and neurocytotoxicity. In the intracerebral hemorrhage model, it improves behavioral outcomes and increases survival with greater efficacy than a pharmacologic benchmark. The protocol satisfies Food and Drug Administration safety guidelines, supporting clinical translatability. If demonstrated effective clinically, it may provide therapeutic benefit not only in hemorrhagic stroke but also in other neurologic disorders that involve impaired debris clearance. Biomedical engineering Stroke biology mouse experiments
N Nature Biotechnology · Nov 05, 2025 A nonsurgical brain implant enabled through a cell–electronics hybrid for focal neuromodulation Bioelectronic implants for brain stimulation are used to treat brain disorders but require invasive surgery. To provide a noninvasive alternative, we report nonsurgical implants consisting of immune cell–electronics hybrids, an approach we call Circulatronics. The devices can be delivered intravenously and traffic autonomously to regions of inflammation in the brain, where they implant and enable neuromodulation, circumventing the need for surgery. To achieve suitable electronics, we designed and built subcellular-sized, wireless, photovoltaic electronic devices that harvest optical energy with high power conversion efficiency. In mice, we demonstrate nonsurgical implantation in an inflamed brain region, as an example of therapeutic target for several neural diseases, by employing monocytes as cells, covalently attaching them to the subcellular-sized, wireless, photovoltaic electronic devices and administering the resulting hybrids intravenously. We also demonstrate neural stimulation with 30-µm precision around the inflamed region. Thus, by fusing electronic functionality with the biological transport and targeting capabilities of living cells, this technology can form the foundation for autonomously implanting bioelectronics. Biomedical engineering Biotechnology biology mouse experiments
N Nature Biotechnology · Oct 17, 2025 A tumor-on-a-chip for in vitro study of CAR-T cell immunotherapy in solid tumors Our limited understanding of cancer–immune interactions remains a critical barrier to advancing chimeric antigen receptor (CAR)-T cell therapy for solid malignancies. Here, we present a microengineered system that enables vascularization of human tumor explants and their controlled perfusion with immune cells to model the activity of CAR-T cells in the tumor microenvironment. Using vascularized human lung adenocarcinoma tumors, we first demonstrate the ability of our tumor-on-a-chip system to simulate, visualize and interrogate CAR-T cell function. We then test a chemokine-directed CAR-T cell engineering strategy in a model of malignant pleural mesothelioma and validate our findings in a matching in vivo mouse model. Finally, we describe a potential therapeutic target that can be pharmacologically modulated to increase the efficacy of CAR-T cells in lung adenocarcinoma, for which we present biomarkers identified by global metabolomics analysis. Our microphysiological system provides promising in vitro technology to advance the development of adoptive cell therapies for cancer and other diseases. Biomedical engineering Cancer immunotherapy Cancer models Lab-on-a-chip Tissue engineering biology mouse experiments
