Xinjian Fan

An urgent requirement in chimeric antigen receptor (CAR) immune cell therapy [e.g., CAR–natural killer (NK) cells] for solid tumors is to engineer the cells for precise tumor targeting. Meanwhile, medical microrobots can be navigated toward specific target sites using external magnetic fields. Here, by bridging these approaches, we turn CAR-NK cells into magnetic biohybrid microrobots (CAR-NK microrobots) that achieve controllable long-distance targeted navigation at therapeutic doses (∼10 ⁶ cells) in both murine and nonhuman primate animal models in vivo. CAR-NK microrobots are developed through genetic engineering with CAR structures and loading with magnetic nanoparticles for field-based navigation. Different magnetic field inputs reconfigure their swarms between vortex and ribbon modes, allowing dense aggregation for targeted navigation and further broad dispersion for large-area coverage. Using programmable magnetic fields, in vivo CAR-NK microrobot–based therapy is demonstrated for metastatic leptomeningeal carcinomatosis in brain’s cerebrospinal fluid space. After intrathecal injection, the microrobots are magnetically guided long distance through the spinal canal toward the brain in vortex mode and subsequently spread over the target site in ribbon mode, as visualized by real-time angiographic imaging in a nonhuman primate model, providing a proof-of-feasibility demonstration in a nonhuman primate anatomical setting.

The biological environment in vivo is complex, posing a great challenge for the deployment of DNA nanostructure‐based precision nanomedicine. Despite the development of DNA nanostructures responsive to environmental cues, it remains difficult to manipulate DNA with spatiotemporal precision in vivo. Here, inspired by the mechanical unwinding process of DNA in nature, we propose an in vivo dynamic‐torque driven DNA manipulation strategy enabling DNA structural reconfigurations with minute‐scale temporal resolution and centimeter spatial precision. By coupling the rod‐shaped magnetic micromotors (MMs) with a rotating magnetic field (RMF), this strategy enables mechanical DNA manipulation under a low field strength of 20 mT and extends the working distance by an order of magnitude compared to conventional manipulation methods. By orchestrating the RMF frequency, DNA with distinct force thresholds (12–54 pN) and GC contents (22%–100%) can be manipulated precisely. Ultimately, by introducing this strategy in biological systems, a theoretical torque of more than 76.6 nN·nm (an equivalent force of 85.2 pN) can be exerted in the tumor within 5 minutes, therefore manipulating DNA in cellular systems and in vivo efficiently and opening new avenues for precise nanomedicine in complex biological environments.

Intrathecal delivery for central nervous system (CNS) therapy lacks spatiotemporal control due to spinal canal anatomical constraints, especially at human scale. We developed an adaptive magnetic nanorobotic platform enabling multimode swarm mobility for in vivo spinal canal navigation in mice and nonhuman primates. Programmable chain-like, vortex-like, and ribbon-like swarm were accomplished, and vortex swarm was indicated as optimal strategy for adaptive intrathecal navigation. Driven by a robotic arm–generated magnetic field, the vortex swarms indicate navigation within spinal canal over centimeter distances, which magnetically enhanced accumulation at CNS target sites and prolonged their in vivo retention, thereby substantially enhancing their therapeutic efficacy compared with conventional passive intravascular delivery, with minimal side effects. Tests in nonhuman primates indicate that the nanorobotic swarm migration is from the gap between the bundles of cauda equina and then the spin cord, revealing their morphological adaption at the cauda equina interface to circumvent anatomical constraints.

Rate-dependent hysteresis and external disturbances critically constrain the tracking performance and operational stability of piezoelectric nanorobots. This study proposes a hybrid control strategy combining multifrequency feedforward compensation with fuzzy-adaptive feedback control to overcome these limitations. The feedforward component is built upon an enhanced Bouc–Wen model, with parameters accurately identified over the 0.1–20 Hz range via a modified particle swarm optimization, which effectively linearizes the actuator by canceling rate-dependent hysteresis, reducing the maximum tracking error to 0.64% with an RMSE of 0.29%. Building upon this linearized base, a fuzzy-adaptive fast terminal sliding mode controller (Fuzzy-FTSMC) suppresses residual disturbances and model uncertainties. It dynamically adjusts switching gains in real-time via a context-aware fuzzy inference system, thereby balancing finite-time convergence against chattering. Experimental validation confirms the method's efficacy, showing a single-axis repetitive positioning accuracy with a maximum error of 3.5 nm and RMSE below 2.8 nm across amplitudes from 1 $\bm{\mu}$ m down to 50 nm, and multiaxis contour tracking with a maximum error of 4.9 nm and RMSE of 3.9 nm for circular paths. The proposed framework provides an integrated solution that effectively combines multifrequency hysteresis compensation with adaptive feedback control, demonstrating high-precision performance in piezoelectric nanomanipulation tasks.

Autonomous microrobots can reach hard-to-access regions in the human body for minimally invasive therapy. However, their microscale size limits the integration of on-board memory, making their operation dependent on external controls. Here, we develop a magnetic probiotic microrobot integrated with memory-capable genetic circuit to execute autonomous antitumor treatment. Through a one-time magnetic hyperthermia trigger, the biological thermal sensor in the microrobot perceives temperature change and activates the memory module Bxb1-ssrA- attB -P7- attP , transferring the microrobots into a therapeutic state to continuously degrade fibrin and soften the tumor microenvironment. The genetic memory remains active for at least 12 days. A synergy toward deep tumor penetration is subsequently established between the memory-encoded softening and the physical penetration through magnetically controlled wave-like locomotion of microrobots. Compared with memory-absent microrobots, the proposed microrobots achieve a 6.70-fold tumor matrix stiffness reduction and boost in vivo anticancer efficacy from 21.86 to 87.52%. Beyond oncology, the proposed system establishes a generalizable framework of memory-encoded medical microrobots.

Magnetically controlled soft microrobots, by virtue of their exceptional flexibility and noninvasiveness, exhibit immense potential in the field of minimally invasive diagnosis and treatment within complex physiological environments. However, existing microrobot research is largely limited to the integration of single functions, and often faces bottlenecks such as insufficient pinpointing ability and difficulty in transmucosal drug delivery when encountering slippery and dynamic biological barriers like the gastrointestinal tract. Here, inspired by the grasping, jetting, and adhesive characteristics of squid tentacles, we report an integrated, multifunctional Squid-Inspired Retainable Magnetic Robot (SRMR). By employing a spatially programmable magnetization distribution and a gradient magnetic powder loading strategy, the SRMR is capable of reconfiguring its locomotion modes according to topographical requirements, enabling cross-scale motion control and functional execution. Results demonstrate that the SRMR possesses the ability to move stably in unstructured environments, utilizing rotating, swinging, and conical magnetic fields to transition between multiple modes, including rolling, walking, and even jumping. By integrating a drug delivery module based on swellable materials and microneedle arrays, the SRMR can precisely penetrate mucosal barriers under the drive of instantaneous gradient magnetic forces, achieving the active delivery of macromolecular drugs. Furthermore, combined with a “dry-wet synergistic” retention strategy, the robot can not only dexterously encapsulate and transport foreign bodies within the digestive tract but also maintain robust positional stability under complex fluid flushing. This microrobotic system, which integrates multimodal locomotion, foreign body handling, and transmucosal drug delivery, holds great promise for future wireless medical intervention tasks within confined regions of the human body.

Intrinsic physiological barriers impede the effective accumulation of locally acting drugs at target spots, and overcoming these physiological obstacles has become a major bottleneck limiting the advancement of targeted drug delivery systems. Existing drug-loaded micro/nanorobots attempt to adapt to the physiological environment. However, they encounter challenges in balancing actuation performance, controlled drug release and biological compatibility. Inspired by the attachment behavior of North American opossum, we present a magnetically driven mother-child robot (MCR) system: the mother robot (MR) uses NdFeB as the core to achieve strong magnetic response and load-bearing capacity, while the child robots (CRs) use Fe₃O₄-gelatin as the matrix to ensure biocompatibility and drug-loading functionality. The MCR can exhibit behaviors such as trench crossing, gap passing, and obstacle climbing that CRs cannot accomplish independently. Employing the excised porcine stomach with relatively complex physiological environments as the experimental model, coupled with a large-space magnetic control system and ultrasonic detection system, MCR enables directional navigation and controllable exfoliation of CRs. Through acid-resistant modification with calcium carbonate (CaCO₃) and stimulation by near-infrared (NIR) laser and magnetic field, the CRs possess structural stability in acidic environments and drug controlled-release. The MCR system offers an innovative solution that can break through complex physiological barriers and drive the development of targeted drug delivery technology.

Four-dimensional (4D) printing couples additive manufacturing with stimuli-responsive materials to create soft microrobots that can be programmed to change their shape, properties, and functions in response to external cues. This review synthesizes the core blueprint for 4D-printed soft microrobots, encompassing printing technologies, smart materials, and stimulus modalities. It explores how these elements collectively design locomotion, manipulation, and sensing at the microscale, and investigates application frontiers including targeted drug delivery, tissue engineering, stents, sensing, and other applications. Despite rapid progress, key obstacles remain, such as resolution-throughput-multimaterial trade-offs, interlayer adhesion, long-term fidelity, limited force density, biocompatibility, near-body-temperature triggers, and closed-loop imaging and navigation. Our conclusion is that 4D printing provides a unifying platform for adaptive, reconfigurable soft microrobots, and coordinated advances in materials, manufacturing, modeling, and regulation are essential for unlocking reliable clinical and industry-relevant systems.

Combination therapy is a promising approach to enhancing antitumor efficacy and overcoming multidrug resistance. Intravesical instillation of Bacillus Calmette–Guérin (BCG) combined with chemotherapy has been employed to improve bladder cancer treatment efficacy, but outcomes are often limited by high-dose drug irritation, poor patient tolerance, and insufficient targeting. To overcome these limitations, we propose a microrobot (MR)-based targeted drug delivery strategy for precise co-delivery of BCG and paclitaxel to bladder tumors, facilitating sustained drug release and minimizing off-target effects. The MRs are fabricated using a layer-by-layer assembly technique, incorporating antitumor drugs, magnetic nanoparticles, and viable BCG. Under the synergistic action of external magnetic fields and hydrogen microbubbles generated through chemical reactions, the MRs achieve targeted navigation and effective accumulation within the 3-dimensional tumor microenvironment. Subsequently, the combined chemotherapeutic and immunostimulatory effects effectively inhibit tumor progression. This approach not only minimizes off-target effects but also facilitates sustained drug release. Additionally, a wearable magnetic fixation device based on a Halbach array is employed to fixate the MRs at the targeted region, further improving drug retention and enhancing therapeutic efficacy. The experimental results demonstrate that this MR-based delivery system holds considerable potential for clinical translation into combination therapies for bladder cancer.