Self-propelled nanomotors with Janus asymmetry represent a transformative approach to active drug delivery, overcoming diffusion-limited transport and enhancing tissue penetration through autonomous motion. These microscale and nanoscale devices exploit asymmetric surface chemistry or geometry to generate propulsive forces, enabling targeted delivery in complex biological environments. The unique feature of Janus nanomotors lies in their bipartite structure, where two distinct hemispheres perform different functions—one facilitates propulsion while the other carries therapeutic payloads or targeting ligands.

The propulsion mechanisms of Janus nanomotors are primarily driven by chemical or physical asymmetry. Catalytic decomposition of hydrogen peroxide (H2O2) is a widely studied method, where platinum-coated hemispheres catalyze the breakdown of H2O2 into oxygen and water. The resulting oxygen bubbles create a local concentration gradient, generating thrust in the opposite direction. Speeds ranging from 10 to 100 body lengths per second have been reported for Pt-based Janus particles in H2O2 solutions, depending on particle size and fuel concentration. Light-driven propulsion offers an alternative, eliminating the need for chemical fuels. Asymmetric metal coatings, such as gold or titanium dioxide, absorb light and induce localized thermal gradients or photocatalytic reactions, propelling the particle via self-electrophoresis or self-thermophoresis. Near-infrared light is particularly advantageous for biomedical applications due to its deeper tissue penetration and reduced phototoxicity.

Directional movement is critical for enhancing tissue penetration, especially in dense extracellular matrices or tumor microenvironments where passive diffusion is inefficient. Janus nanomotors exhibit enhanced penetration depths compared to static nanoparticles, with studies demonstrating up to fivefold increases in tumor spheroid infiltration. The autonomous motion allows these particles to navigate physiological barriers, such as mucus layers or blood-brain barrier models, through sustained propulsion forces. Magnetic fields can further guide Janus motors, combining external control with self-propulsion for precise navigation.

Design strategies for Janus nanomotors focus on optimizing propulsion efficiency while maintaining biocompatibility. Common fabrication methods include physical vapor deposition, where metals like Pt or Au are selectively deposited on one hemisphere of silica or polymer particles. Asymmetric polymer coatings can also generate self-diffusiophoretic motion in response to ionic gradients. Core-shell designs incorporate a functionalized inner core for drug loading and an outer Janus layer for propulsion. For example, mesoporous silica particles half-coated with catalytic metals enable high drug payloads while maintaining efficient motion. Size optimization is crucial—particles between 200 nm and 2 µm balance propulsion efficiency with cellular uptake and circulation times.

Payload release mechanisms are engineered to respond to specific triggers, ensuring controlled delivery at target sites. Chemically propelled Janus motors often rely on fuel depletion to slow down and release drugs passively upon reaching low H2O2 concentrations. Stimuli-responsive polymers, such as pH-sensitive hydrogels or thermoresponsive poly(N-isopropylacrylamide), can be incorporated to release drugs in acidic tumor microenvironments or upon light-induced heating. Enzymatic cleavage of drug-polymer conjugates provides another release pathway, leveraging overexpressed enzymes in diseased tissues. Some designs exploit the propulsion mechanism itself—bubble propulsion can enhance convective mixing, accelerating drug diffusion from the particle surface.

In vivo applications face significant challenges, including biocompatibility, propulsion in physiological fluids, and immune clearance. H2O2-fueled systems are limited by the toxic fuel concentrations required for sustained motion, though endogenous H2O2 in inflamed tissues may partially address this. Light-driven motors face scattering and absorption in biological tissues, necessitating upconversion nanoparticles or two-photon excitation for deeper activation. Protein fouling on motor surfaces can impede propulsion, prompting the use of PEGylation or zwitterionic coatings to reduce biofouling. Immune recognition remains a hurdle, with studies showing rapid clearance of certain metal-coated motors by the reticuloendothelial system. Biodegradable Janus motors, such as those made from magnesium or poly(lactic-co-glycolic acid), aim to mitigate long-term toxicity concerns.

Recent advances focus on hybrid propulsion systems and biohybrid designs. Combining magnetic guidance with catalytic or light-driven motion enhances directional control in vivo. Biohybrid Janus motors, incorporating bacteria or sperm cells as natural propellers, leverage biological mechanisms for improved biocompatibility and tissue penetration. These systems have demonstrated enhanced drug delivery in preclinical models, particularly in gastrointestinal and reproductive tract applications.

The future of Janus nanomotors lies in overcoming biological barriers while maintaining efficient propulsion and controlled release. Advances in materials science, such as the development of fuel-free propulsion mechanisms and biodegradable components, will be critical for clinical translation. Computational modeling of motor trajectories in complex fluids and tissues can further optimize designs for specific applications. As these challenges are addressed, self-propelled Janus nanomotors hold promise for revolutionizing targeted drug delivery in oncology, neurology, and regenerative medicine.