Towards multifunctional robotic pills.

Robotic pills leverage the advantages of oral pharmaceutical formulations-in particular, convenient encapsulation, high loading capacity, ease of manufacturing and high patient compliance-as well as the multifunctionality, increasing miniaturization and sophistication of microrobotic systems. In this Perspective, we provide an overview of major innovations in the development of robotic pills-specifically, oral pills embedded with robotic capabilities based on microneedles, microinjectors, microstirrers or microrockets-summarize current progress and applicational gaps of the technology, and discuss its prospects. We argue that the integration of multiple microrobotic functions within oral delivery systems alongside accurate control of the release characteristics of their payload provides a basis for realizing sophisticated multifunctional robotic pills that operate as closed-loop systems.

A Microstirring Oral Pill for Improving the Glucose-Lowering Effect of Metformin.

Type 2 diabetes mellitus (T2DM) is characterized by hyperglycemia due to persistent insulin resistance, resulting in elevated blood glucose levels. Metformin is the most prescribed oral drug for lowering high blood glucose levels in T2DM patients. However, it is poorly absorbed and has low bioavailability. Here, we introduce magnesium-based microstirrers to a metformin-containing pill matrix to enhance the glucose-lowering effect of metformin. The resulting microstirring pill possesses a built-in mixing capability by creating local fluid transport upon interacting with biological fluid to enable fast pill disintegration and drug release along with accelerated metformin delivery. In vivo glucose tolerance testing using a murine model demonstrates that the metformin microstirring pill significantly improves therapeutic efficacy, lowering blood glucose levels after a meal more rapidly compared to a regular metformin pill without active stirring. As a result, the microstirrers allow for dose sparing, providing effective therapeutic efficacy at a lower drug dosage than passive metformin pills. These encouraging results highlight the versatility of this simple yet elegant microstirring pill technology, which enhances drug absorption after gastrointestinal delivery to improve therapeutic efficacy.

Using Cell Membranes as Recognition Layers to Construct Ultrasensitive and Selective Bioelectronic Affinity Sensors.

Conventional sandwich immunosensors rely on antibody recognition layers to selectively capture and detect target antigen analytes. However, the fabrication of these traditional affinity sensors is typically associated with lengthy and multistep surface modifications of electrodes and faces the challenge of nonspecific adsorption from complex sample matrices. Here, we report on a unique design of bioelectronic affinity sensors by using natural cell membranes as recognition layers for protein detection and prevention of biofouling. Specifically, we employ the human macrophage (MΦ) membrane together with the human red blood cell (RBC) membrane to coat electrochemical transducers through a one-step process. The natural protein receptors on the MΦ membrane are used to capture target antigens, while the RBC membrane effectively prevents nonspecific surface binding. In an attempt to detect tumor necrosis factor alpha (TNF-α) cytokine using the bioelectronic affinity sensor, it demonstrates a remarkable limit of detection of 150 pM. This new sensor design integrates natural cell membranes and electronic transduction, which offers synergistic functionalities toward a broad range of biosensing applications.

Gastrointestinal tract drug delivery using algae motors embedded in a degradable capsule.

The use of micromotors for active drug delivery via oral administration has recently gained considerable interest. However, efficient motor-assisted delivery into the gastrointestinal (GI) tract remains challenging, owing to the short propulsion lifetime of currently used micromotor platforms. Here, we report on an efficient algae-based motor platform, which takes advantage of the fast and long-lasting swimming behavior of natural microalgae in intestinal fluid to prolong local retention within the GI tract. Fluorescent dye or cell membrane-coated nanoparticle functionalized algae motors were further embedded inside a pH-sensitive capsule to enhance delivery to the small intestines. In vitro, the algae motors displayed a constant motion behavior in simulated intestinal fluid after 12 hours of continuous operation. When orally administered in vivo into mice, the algae motors substantially improved GI distribution of the dye payload compared with traditional magnesium-based micromotors, which are limited by short propulsion lifetimes, and they also enhanced retention of a model chemotherapeutic payload in the GI tract compared with a passive nanoparticle formulation. Overall, combining the efficient motion and extended lifetime of natural algae-based motors with the protective capabilities of oral capsules results in a promising micromotor platform capable of achieving greatly improved cargo delivery in GI tissue for practical biomedical applications.

Biomembrane-Functionalized Micromotors: Biocompatible Active Devices for Diverse Biomedical Applications.

There has been considerable interest in developing synthetic micromotors with biofunctional, versatile, and adaptive capabilities for biomedical applications. In this perspective, cell membrane-functionalized micromotors emerge as an attractive platform. This new class of micromotors demonstrates enhanced propulsion and compelling performance in complex biological environments, making them suitable for various in vivo applications, including drug delivery, detoxification, immune modulation, and phototherapy. This article reviews various proof-of-concept studies based on different micromotor designs and cell membrane coatings in these areas. The review focuses on the motor structure and performance relationship and highlights how cell membrane functionalization overcomes the obstacles faced by traditional synthetic micromotors while imparting them with unique capabilities. Overall, the cell membrane-functionalized micromotors are expected to advance micromotor research and facilitate its translation towards practical uses.

Physical Disruption of Solid Tumors by Immunostimulatory Microrobots Enhances Antitumor Immunity.

The combination of immunotherapy with other forms of treatment is an emerging strategy for boosting antitumor responses. By combining multiple modes of action, these combinatorial therapies can improve clinical outcomes through unique synergisms. Here, a microrobot-based strategy that integrates tumor tissue disruption with biological stimulation is shown for cancer immunotherapy. The microrobot is fabricated by loading bacterial outer membrane vesicles onto a self-propelling micromotor, which can react with water to generate a propulsion force. When administered intratumorally to a solid tumor, the disruption of the local tumor tissue coupled with the delivery of an immunostimulatory payload leads to complete tumor regression. Additionally, treatment of the primary tumor results in the simultaneous education of the host immune system, enabling it to control the growth of distant tumors. Overall, this work introduces a distinct application of microrobots in cancer immunotherapy and offers an attractive strategy for amplifying cancer treatment efficacy when combined with conventional therapies.

A Microstirring Pill Enhances Bioavailability of Orally Administered Drugs.

Majority of drugs are administered orally, yet their efficient absorption is often difficult to achieve, with a low dose fraction reaching the blood compartment. Here, a microstirring pill technology is reported with built-in mixing capability for oral drug delivery that greatly enhances bioavailability of its therapeutic payload. Embedding microscopic stirrers into a pill matrix enables faster disintegration and dissolution, leading to improved release profiles of three widely used model drugs, aspirin, levodopa, and acetaminophen, without compromising their loading. Unlike recently developed drug-carrying nanomotors, drug molecules are not associated with the microstirrers, and hence there is no limitation on the loading capacity. These embedded microstirrers are fabricated through the asymmetric coating of titanium dioxide thin film onto magnesium microparticles. In vitro tests illustrate that the embedded microstirrers lead to substantial enhancement of local fluid transport. In vivo studies using murine and porcine models demonstrate that the localized stirring capability of microstirrers leads to enhanced bioavailability of drug payloads. Such improvements are of considerable importance in clinical scenarios where fast absorption and high bioavailability of therapeutics are critical. The encouraging results obtained in porcine model suggest that the microstirring pill technology has translational potential and can be developed toward practical biomedical applications.

ACE2 Receptor-Modified Algae-Based Microrobot for Removal of SARS-CoV-2 in Wastewater.

The coronavirus SARS-CoV-2 can survive in wastewater for several days with a potential risk of waterborne human transmission, hence posing challenges in containing the virus and reducing its spread. Herein, we report on an active biohybrid microrobot system that offers highly efficient capture and removal of target virus from various aquatic media. The algae-based microrobot is fabricated by using click chemistry to functionalize microalgae with angiotensin-converting enzyme 2 (ACE2) receptor against the SARS-CoV-2 spike protein. The resulting ACE2-algae-robot displays fast (>100 µm/s) and long-lasting (>24 h) self-propulsion in diverse aquatic media including drinking water and river water, obviating the need for external fuels. Such movement of the ACE2-algae-robot offers effective "on-the-fly" removal of SARS-CoV-2 spike proteins and SARS-CoV-2 pseudovirus. Specifically, the active biohybrid microrobot results in 95% removal of viral spike protein and 89% removal of pseudovirus, significantly exceeding the control groups such as static ACE2-algae and bare algae. These results suggest considerable promise of biologically functionalized algae toward the removal of viruses and other environmental threats from wastewater.

Zinc Microrocket Pills: Fabrication and Characterization toward Active Oral Delivery.

Here the fabrication of a zinc (Zn) microrocket pill is reported, and its unique features toward active and enhanced oral delivery application are demonstrated. By loading Zn-based tubular microrockets into an orally administrable pill formulation, the resulting Zn microrocket pill can rapidly dissolve in the stomach, releasing numerous encapsulated Zn microrockets that are instantaneously activated and then propel in the gastric fluid. The released Zn microrockets display efficient propulsion without being affected by the presence of the inactive excipient materials of the pill. An in vivo retention study performed in mice clearly shows that the active pill dissolution and powerful acid-driven Zn microrocket propulsion greatly enhance the microrocket retention within the gastric tissue without causing toxic effects. By combining the active delivery feature of Zn microrockets with the oral administration of a pill, the Zn microrocket pill holds considerable potential for active oral delivery of various therapeutics for diverse medical applications.

Multicompartment Tubular Micromotors Toward Enhanced Localized Active Delivery.

A tubular micromotor with spatially resolved compartments is presented toward efficient site-specific cargo delivery, with a back-end zinc (Zn) propellant engine segment and an upfront cargo-loaded gelatin segment further protected by a pH-responsive cap. The multicompartment micromotors display strong gastric-powered propulsion with tunable lifetime depending on the Zn segment length. Such propulsion significantly enhances the motor distribution and retention in the gastric tissues, by pushing and impinging the front-end cargo segment onto the stomach wall. Once the micromotor penetrates the gastric mucosa (pH ≥ 6.0), its pH-responsive cap dissolves, promoting the autonomous localized cargo release. The fabrication process, physicochemical properties, and propulsion behavior are systematically tested and discussed. Using a mouse model, the multicompartment motors, loaded with a model cargo, demonstrate a homogeneous cargo distribution along with approximately four-fold enhanced retention in the gastric lining compared to monocompartment motors, while showing no apparent toxicity. Therapeutic payloads can also be loaded into the pH-responsive cap, in addition to the gelatin-based compartment, leading to concurrent delivery and sequential release of dual cargos toward combinatorial therapy. Overall, this multicompartment micromotor system provides unique features and advantages that will further advance the development of synthetic micromotors for active transport and localized delivery of biomedical cargos.

Active Delivery of VLPs Promotes Anti-Tumor Activity in a Mouse Ovarian Tumor Model.

Virus-like nanoparticles (VLPs) have been used as an attractive means in cancer immunotherapy because of their unique intrinsic immunostimulatory properties. However, for treating metastatic tumors in the peritoneal cavity, such as ovarian cancer, multiple injections of therapy are needed due to the large peritoneal space and fast excretion of therapy. Here, it is reported on the development of active VLP delivery vehicles for the treatment of peritoneal ovarian tumors using biocompatible Qß VLPs-loaded Mg-based micromotors. The autonomous propulsion of such Qß VLPs-loaded Mg-micromotors in the peritoneal fluid enables active delivery of intact immunostimulatory Qß VLPs to the peritoneal space of ovarian tumor bearing mice, greatly enhancing the local distribution and retention of Qß VLPs. Such improved distribution and longer retention time of Qß in the peritoneal cavity leads to enhanced immunostimulation and therefore increased survival rate of tumor-bearing mice compared to a passive Qß treatment. For clinical translation, the active delivery of VLPs holds great promise for tumor immunotherapy toward the treatment of different types of primary and metastatic tumors in the peritoneal cavity.

Micromotors for Active Delivery of Minerals toward the Treatment of Iron Deficiency Anemia.

As the most common nutritional disorder, iron deficiency represents a major public health problem with broad impacts on physical and mental development. However, treatment is often compromised by low iron bioavailability and undesired side effects. Here, we report on the development of active mineral delivery vehicles using Mg-based micromotors, which can autonomously propel in gastrointestinal fluids, aiding in the dynamic delivery of minerals. Iron and selenium are combined as a model mineral payload in the micromotor platform. We demonstrate the ability of our mineral-loaded micromotors to replenish iron and selenium stores in an anemic mouse model after 30 days of treatment, normalizing hematological parameters such as red blood count, hemoglobin, and hematocrit. Additionally, the micromotor platform exhibits no toxicity after the treatment regimen. This proof-of-concept study indicates that micromotor-based active delivery of mineral supplements represents an attractive approach toward alleviating nutritional deficiencies.

A Macrophage-Magnesium Hybrid Biomotor: Fabrication and Characterization.

Magnesium (Mg)-based micromotors are combined with live macrophage (MΦ) cells to create a unique MΦ-Mg biohybrid motor system. The resulting biomotors possess rapid propulsion ability stemming from the Mg micromotors and the biological functions provided by the live MΦ cell. To prepare the biohybrid motors, Mg microparticles coated with titanium dioxide and poly(l-lysine) (PLL) layers are incubated with live MΦs at low temperature. The formation of such biohybrid motors depends on the relative size of the MΦs and Mg particles, with the MΦ swallowing up Mg particles smaller than 5 µm. The experimental results and numerical simulations demonstrate that the motion of MΦ-Mg motors is determined by the size of the Mg micromotor core and the position of the MΦ during the attachment process. The MΦ-Mg motors also perform biological functions related to free MΦs such as endotoxin neutralization. Cell membrane staining and toxin neutralization studies confirm that the MΦs maintain their viability and functionality (e.g., endotoxin neutralization) after binding to the Mg micromotors. This new MΦ-Mg motor design can be expanded to different types of living cells to fulfill diverse biological tasks.

Micromotor Pills as a Dynamic Oral Delivery Platform.

Tremendous progress has been made during the past decade toward the design of nano/micromotors with high biocompatibility, multifunctionality, and efficient propulsion in biological fluids, which collectively have led to the initial investigation of in vivo biomedical applications of these synthetic motors. Despite these recent advances in micromotor designs and mechanistic research, significant effort is needed to develop appropriate formulations of micromotors to facilitate their in vivo administration and thus to better test their in vivo applicability. Herein, we present a micromotor pill and demonstrate its attractive use as a platform for in vivo oral delivery of active micromotors. The micromotor pill is comprised of active Mg-based micromotors dispersed uniformly in the pill matrix, containing inactive (lactose/maltose) excipients and other disintegration-aiding (cellulose/starch) additives. Our in vivo studies using a mouse model show that the micromotor pill platform effectively protects and carries the active micromotors to the stomach, enabling their release in a concentrated manner. The micromotor encapsulation and the inactive excipient materials have no effects on the motion of the released micromotors. The released cargo-loaded micromotors propel in gastric fluid, retaining the high-performance characteristics of in vitro micromotors while providing higher cargo retention onto the stomach lining compared to orally administrated free micromotors and passive microparticles. Furthermore, the micromotor pills and the loaded micromotors retain the same characteristics and propulsion behavior after extended storage in harsh conditions. These results illustrate that combining the advantages of traditional pills with the efficient movement of micromotors offer an appealing route for administrating micromotors for potential in vivo biomedical applications.