Drug Deliery for Micro-/Nanorobots: Progress and Challenges

As a typical microscopic imaging technology, the emergence of the microscope has accelerated the pace of human exploration of the micro world. With the development of science and technology, microscopes have developed from the optical microscopes at the time of their invention to electron microscopes and even atomic force microscopes. The resolution has steadily improved, allowing humans to expand the field of research from the initial animal and plant tissues to microorganisms such as bacteria, and even down to the nanolevel. The microscope is now widely used in life science, material science, geological research, and other fields. It can be said that the development of microscopes also promotes the development of micro- and nanotechnology. It is foreseeable that microscopes will play a significant part in the exploration of the microworld for a long time to come. The development of microscope technology is the focus of this study, which summarized the properties of numerous microscopes and discussed their applications in micro and nanotechnology. At the same time, the application of microscopic imaging technology in micro- and nanofields was investigated based on the properties of various microscopes.

Micro‐ and nanomotors are synthetic devices that can transform various sources of energy into motion. These devices perform specialized tasks as they propel themselves in response to stimuli. The application of self‐propelled micro‐ and nanomachines in wastewater treatment has been of prime importance in the last decade. Compared to static decontamination systems, micro‐ and nanomachines can remove or degrade water pollutants in a much more rapid way owing to higher diffusion rates and fluxes. The present review focuses on the recent progress of micro‐ and nanomachines in wastewater treatment and provides an overview of their structural features, synthesis procedures, and propulsion mechanisms. We reviewed the applications of micro‐ and nanomachines to remove heavy metals, dyes, and organic pollutants from wastewater. We also discussed the challenges micro‐ and nanomotors face during wastewater treatment, thus providing a holistic approach to the article. This article highlights the shortcomings as well as the opportunities for micro‐ and nanomotors‐based technology in wastewater treatment.

Advances in new micro- and nanotechnologies are accelerating the identification and evaluation of drug candidates, and the development of new delivery technologies that are required to transform biological potential into medical reality. This article will highlight the emerging micro- and nanotechnology tools, techniques and devices that are being applied to advance the fields of drug discovery and drug delivery. Many of the promising applications of micro- and nanotechnology are likely to occur at the interfaces between microtechnology, nanotechnology and biochemistry.

9 - BioMEMs for drug delivery applications

Micro- and nano-electromechanical systems (MEMS and NEMS)-based drug delivery devices have become commercially-feasible due to converging technologies and regulatory accommodation. The FDA Office of Combination Products coordinates review of innovative medical therapies that join elements from multiple established categories: drugs, devices, and biologics. Combination products constructed using MEMS or NEMS technology offer revolutionary opportunities to address unmet medical needs related to dosing. These products have the potential to completely control drug release, meeting requirements for on-demand pulsatile or adjustable continuous administration for extended periods. MEMS or NEMS technologies, materials science, data management, and biological science have all significantly developed in recent years, providing a multidisciplinary foundation for developing integrated therapeutic systems. If small-scale biosensor and drug reservoir units are combined and implanted, a wireless integrated system can regulate drug release, receive sensor feedback, and transmit updates. For example, an "artificial pancreas" implementation of an integrated therapeutic system would improve diabetes management. The tools of microfabrication technology, information science, and systems biology are being combined to design increasingly sophisticated drug delivery systems that promise to significantly improve medical care.

Self-propelled micro-/nanomotors (MNMs), which are defined as micro-/nanodevices capable of converting various energy into autonomous motion, can be used to pick up, transport, and release various cargoes within a liquid medium. They have important potential applications, for example, in drug delivery, biosensors, protein and cell separation, microsurgeries and environment remediation. This review comprehensively introduces the design strategies and structures of self-propelled MNMs along with an outlook for their future development. It starts with the summary of the propulsion mechanisms of self-propelled MNMs of bubble recoiling and self-phoresis induced by the asymmetric release of products or heat. For bubble recoiling propulsion, the continuous momentum change is caused by a jet of bubbles, while for self-phoresis propulsion, the MNMs move in a local electric field, concentration gradient, surface tension gradient, or temperature gradient, etc. After systematically and in-depth understanding these propulsion mechanisms, it has been pointed out that the key to design self-propelled MNMs is to construct an asymmetric field across micro-/ nanoparticles. Following this clue, the structures evolution and simplification methods of self-propelled MNMs are reviewed. Janus structures and multilayer-tubular structures, which are prepared through asymmetric modification process, electrochemical synthesis, template-assisted method, rolled-up nanotech, etc., have been firstly proposed to construct asymmetric fields across micro-/nanoparticles for their propulsion. However, the complicated structure and preparation process hinder the application of MNMs. Anisotropic single-component irregular particles, tubes and bowl-like MNMs, which are obtained by dry spinning method, “growing-bubble”-templated self-assembly, etc., have been subsequently achieved by utilizing their anomalous morphology and the nucleation preference of bubble molecules on different surfaces. This kind of MNMs show somewhat simple structure and can be easily fabricated, but the motion direction is still difficult to control because of the Brownian motion. Isotropic semiconducting MNMs have been recently developed by taking advantage of the limited light penetration depth in the isotropic photoresponsive particles, of which the motion is independent of the rotational Brownian motion. This suggests a remarkable breakthrough in design strategy of MNMs due to the simple isotropic structure of the motor and the controllability in both motion direction and speed by light. Besides the evolution of self-propelled MNMs from the complicated structure to the simplified one, some remarkable progresses have also been made on the motion control, functionalization, etc. For example, the speed and state of MNMs can so far be easily adjusted by the concentration of fuels, the intensity of external fields, etc. The direction can be controlled accurately by magnetic field, electric field, light, etc. Numerous complex tasks can also be performed effectively, such as protein separation, drug delivery, environmental detection and remediation, etc. Lastly, an outlook is also provided on the future development and main challenges of self-propelled MNMs. The future development of MNMs should be focused on improving energy conversion efficiency through optimization of structures, exploring new propulsion mechanisms and endowing MNMs with environmental responses for self-navigation, detection, and specific operations. In this way, MNMs will approach to the practical applications in biomedicine, environment treatment, microengineering, etc.

Retinal drug delivery using eyedrop preparations of poly-l-lysine-modified liposomes

The application of micro- and nanotechnology to the biomedical arena has tremendous potential in terms of developing new diagnostic and therapeutic modalities. Recent advances in micromachining and microelectriomechanical systems (MEMS) technology have provided the opportunity to fabricate miniature biomedical devices for a variety of applications. While the majority of research has focused on the development of miniaturized diagnostic tools, researchers have more recently concentrated on the development of microdevices for therapeutic applications. The progression of microfabrication technology has enabled the creation of entirely new classes of drug delivery devices which can possess a combination of structural, mechanical, chemical, and electronic features to surmount the challenges associated with conventional systems. Some therapeutic applications of microtechnology include microneedles for transdermal delivery [1, 2], as well as various implantable systems, such as immunoisolating biocapules [3, 4] and microchips for controlled release [5, 6]. However in this research, the strengths of microfabrication and micromachining were capitalized to create a completely novel microdevice from silicon dioxide, porous silicon, and poly(methyl methacrylate) for cytoadhesive oral drug delivery with inherent features providing controlled release.

The intensive development of micro- and nanotechnologies in recent years has offered a wide horizon of new possibilities for drug delivery in dentistry. The use of polymeric drug carriers turned out to be a very successful technique for formulating micro- and nanoparticles with controlled or targeted drug release in the oral cavity. Such innovative strategies have the potential to provide an improved therapeutic approach to prevention and treatment of various oral diseases not only for adults, but also in the pediatric dental practice. Due to their biocompatibility, biotolerance and biodegradability, naturally occurring polysaccharides like chitosan, alginate, pectin, dextran, starch, etc., are among the most preferred materials for preparation of micro- and nano-devices for drug delivery, offering simple particle-forming characteristics and easily tunable properties of the formulated structures. Their low immunogenicity and low toxicity provide an advantage over most synthetic polymers for the development of pediatric formulations. This review is focused on micro- and nanoscale polysaccharide biomaterials as dental drug carriers, with an emphasis on their potential application in pediatric dentistry.

Rapid drug delivery is critical in emergency medical circumstances where delays can result in adverse or life-threatening outcomes. The sublingual route holds significant promise for the swift systemic delivery of drugs, but is limited by slow passive diffusion mechanisms that hinder efficient drug transport. To address these challenges, we introduce here a novel sublingual microrobotic pill platform designed for rapid and efficient drug delivery. Our system incorporates magnesium-based microstirrers that accelerate pill disintegration and drug release via an active propulsion mechanism. Such bubble-propelled microstirrers generate strong hydrodynamic flows, enhancing local mixing and drug transport, allowing them to overcome the limitations of traditional diffusion-dominated delivery systems. Optimized through in vitro studies, this platform demonstrated robust motion capabilities in complex human saliva and accelerated drug release kinetics. In a rabbit model, using epinephrine as the model drug, the sublingual microrobotic pill achieved significantly faster drug delivery speed, efficiency, and bioavailability compared to a conventional pill. Moreover, when compared against the gold standard intramuscular injections, the microstirring pill provides competitive delivery speed and enhanced absorption profile, demonstrating its potential for use in the treatment of conditions like anaphylactic shock. Such user-friendly, non-invasive sublingual microrobotic pills can be readily employed for delivering a wide range of drugs, offering a versatile solution for acute conditions requiring rapid therapeutic onset or when enteral absorption is not feasible.

The successful chemotherapeutic regime required for the clinical management of different cancers largely depends on the efficient drug delivery within the cancer cells. Exosomes have emerged as an enticing candidate for exploring their role as delivery vehicles. Exosomes are reported to be intrinsically nanosized vesicles competent for efficient delivery across the cellular membrane. In the present study, we assessed the feasibility of an autologous exosome-based drug delivery platform for delivering 5-Fluorouracil (5-FU) against human colon cancer HCT116 cells. Autologous exosomes have shown probable tropism toward the tumor microenvironment, which makes them the most competitive vehicle for drug delivery. It was observed that the autologous exosomes loaded with 5-FU showed an enhanced rate of drug release under acidic conditions. The result of the cell viability assay showed that treatment of 5-FU-loaded exosomes (equivalent to 5μg 5-FU) resulted in enhanced cytotoxic effect in HCT116 cells as compared to an equivalent amount of free 5-FU (5μg), which elucidated the efficient delivery of the 5-FU by exosomes inside the cancer cells. Subsequently, 5-FU-loaded exosomes led to increased nuclear condensation and fragmentation along with increased ROS production. In addition, 5-FU-loaded exosomes caused enhanced dissipation of mitochondrial membrane potential and caspase-3 activation, resulting in increased apoptosis induction. Our study also revealed that 5-FU-loaded exosomes upsurged the arrest in the cell cycle at the G0/G1 stage in HCT-116 cells and it was found to be associated with decreased CDK4 and Cyclin D1 expression concomitantly with the upregulation of CDK inhibitor, p21Cip1 expression. Thus, the findings from the present study highlight the advantages of autologous exosomes as a natural drug carrier which could efficiently deliver chemotherapeutic drugs to cancer cells.

Chapter 11 - Carbon dots as carriers for the development of controlled drug and gene delivery systems

The review of nasal drug delivery system: The strategies to enhance the efficiency of intranasal drug delivery by improving drug absorption.

Artificial nanorobots have emerged as promising tools for a wide range of biomedical applications, including biosensing, detoxification, and drug delivery. Their unique ability to navigate confined spaces with precise control extends their operational scope to the cellular or subcellular level. By combining tailored surface functionality and propulsion mechanisms, nanorobots demonstrate rapid penetration of cell membranes and efficient internalization, enhancing intracellular delivery capabilities. Moreover, their robust motion within cells enables targeted interactions with intracellular components, such as proteins, molecules, and organelles, leading to superior performance in intracellular biosensing and organelle-targeted cargo delivery. Consequently, nanorobots hold significant potential as miniaturized surgeons capable of directly modulating cellular dynamics and combating metastasis, thereby maximizing therapeutic outcomes for precision therapy. In this review, we provide an overview of the propulsion modes of nanorobots and discuss essential factors to harness propulsive energy from the local environment or external power sources, including structure, material, and engine selection. We then discuss key advancements in nanorobot technology for various intracellular applications. Finally, we address important considerations for future nanorobot design to facilitate their translation into clinical practice and unlock their full potential in biomedical research and healthcare.

Innovation applications of MXenes in biomedicine