Dual-Spherical Multifunctional Nanomotors for Intravesical Bladder Cancer Therapy: A Comprehensive Review
Introduction
Bladder cancer (BCa) is a prevalent and challenging health issue, especially for non-muscle-invasive cases with high recurrence and progression risks. Postoperative intravesical instillation, a critical adjuvant therapy, improves treatment outcomes and inhibits tumor growth by directly delivering drugs via a catheter into the bladder, allowing them to contact the mucosal surface and reducing systemic toxicity. However, short drug retention times, poor drug penetration, and rapid clearance due to periodic urination often compromise the effectiveness of this approach, leading to suboptimal therapeutic effects and potential cancer recurrence or progression. Radical cystectomy, a surgery with significant impacts on patients' quality of life and prognosis, may be necessary.
Self-powered nanoparticles (nanomotors) have emerged as promising drug delivery systems, offering superior mobility to navigate complex fluid environments, which is typically beyond the reach of drugs and passive nanoparticles. By converting the chemical energy of the surrounding fluid into mechanical thrust, nanomotors enable biomedical applications.
Glucose oxidase (Gox) catalyzes the conversion of glucose to gluconic acid and hydrogen peroxide (H2O2), providing a strategy to modulate tumor glycolysis. However, this reaction consumes oxygen (O2), and hypoxic conditions in tumors can inhibit it. Chen et al. developed a bio-mineralization strategy to create Gox-Mn nanoparticles, combining nanozyme and Gox activities. Manganese-containing nanozymes generate O2 from H2O2 in the tumor microenvironment, supporting Gox's glucose consumption and glycolysis. The generated H2O2 further enhances nanozyme activity, creating a self-amplifying cycle that intensifies glucose depletion and promotes cancer starvation therapy.
Building on this strategy, we developed a novel multifunctional nanomotor (UG-M@Gem) by conjugating Gem-loaded tumor-membrane nanoparticles (M@Gem) with triple-enzyme-active nanoparticles (UG, composed of manganese ions, Gox, and urease). This design leverages the catalytic activities of the enzymes to enhance drug delivery and efficacy. The study simply conjugates drug-loaded membrane nanoparticles with the power source (UG) to achieve asymmetric distribution of urease, maintaining its activity through biomineralization synthesis. Following intravesical instillation, the urease asymmetrically distributed on the nanomotors catalyzes the conversion of urea in urine into carbon dioxide and ammonia, generating a self-propulsion force for rapid nanoparticle movement, enabling deep penetration into the bladder wall. The tumor-membrane homing directs the nanomotors to gather at tumor sites, achieving targeted and deep-penetrating tumor treatment.
Materials and Methods
The synthesis and characterization of the nanomotors involved several steps, including cell membrane derivation, synthesis of cell membrane-coated nanoparticles, synthesis and characterization of UG, synthesis and characterization of UG-M@Gem, and various in vitro and in vivo experiments to assess their properties and efficacy.
Results and Discussion
The UG-M@Gem nanomotors exhibited a uniform dumbbell-shaped structure, with individual M@Gem and UG diameters of 120.6±2.9 nm and 206±3.5 nm, respectively, and the coupled dumbbell structure having a diameter of 310±5.1 nm. Energy-dispersive X-ray spectroscopy (EDS) and X-ray photoelectron spectroscopy (XPS) confirmed the presence of Mn, Ni, and S elements in the tail-end UG structure, consistent with the enzymes' composition. Fourier-transform infrared spectroscopy (FTIR) showed significant differences between UG-M@Gem, M@Gem, and UG, providing direct evidence of successful synthesis. Zeta-potential measurements indicated a more negative surface charge on UG-M@Gem, confirming the conjugation of membrane nanoparticles with UG.
UG-M@Gem demonstrated rapid self-propelled motion in urine, enabling effective penetration of the bladder mucosal barrier and deep tumor-targeted delivery. The specific accumulation of UG-M@Gem in tumor regions and its enhanced tumor penetration ability can be attributed to the directional movement and tumor-targeting properties of the nanomotors.
Conclusion
In summary, the development of dual-spherical nanomotor-based drug delivery platforms for intravesical BCa therapy is a significant advancement. These nanomotors integrate tumor-membrane nanoparticles with tri-enzyme-loaded nanoparticles constructed via biomineralization, offering rapid self-propelled motion in urine, effective bladder mucosal barrier penetration, and deep tumor-targeted delivery. The intravesical instillation of these nanomotors achieved a chemical tumor-resection-like effect in most cases, providing compelling evidence for their potential as a promising platform for BCa treatment and warranting further exploration for clinical translation.
