Dual-Spherical Multifunctional Nanomotors for Intravesical Bladder Cancer Therapy

Yiyang Chen,1,2,* Bin Zheng,1,* Zhenghong Liu,1,* Heng Wang,1 Lihui Xu,3 Xiaowen Qin,1 Li Sun,1 Haichang Li,1 Wentao Xu,1 Yixuan Mou,1 Chenkai Wang,1 Xintao Hua,1 Xuanyi Zhou,1 Dingyi Liu,1 Wenyan Zuo,1 Chunnan Zhang,1 Pu Zhang,1 Dahong Zhang1,2 1Urology & Nephrology Center, Department of Urology, Zhejiang Provincial People’s Hospital (Affiliated People’s Hospital), Hangzhou Medical College, Hangzhou, Zhejiang, People’s Republic of China; 2The Second School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, People’s Republic of China; 3School of Pharmacy, Hangzhou Normal University, Hangzhou, Zhejiang, People’s Republic of China*These authors contributed equally to this workCorrespondence: Pu Zhang, Email zhangpuxjtuer@163.com Dahong Zhang, Email zhangdahong666@163.comBackground: Conventional intravesical chemotherapy for bladder cancer has shown limited clinical efficacy. To overcome this challenge, self-propelled nanomotors, including urease-modified nanomotors, have been developed. These nanomotors enhance drug diffusion in urine, offering advantages over traditional drugs and passive nanoparticles. However, a key issue remains: the inability to maintain long-term urease activity.Methods: Nanozymes, glucose oxidase, and urease are synthesized into a three-enzyme nanomotors via biomineralization, serving as a power source. Cell membrane nanoparticles loaded with gemcitabine were combined with three-enzyme nanomotors to form dual-spherical nanomotors. TEM, DLS, and analyses of urease/glucose oxidase activity and nanomotor trajectories confirmed successful nanomotor fabrication. These nanomotors can regulate tumor cell glucose metabolism and release gemcitabine upon cellular entry, achieving a dual anticancer effect.Results: Nanomotors synthesized through biomineralization methods exhibit the ability to retain long-term activity. After intravesical instillation, urease-containing nanomotors decomposed urea to produce carbon dioxide and ammonia, propelling rapid nanoparticle movement for deep bladder wall penetration. The homing ability of the tumor membrane-coated nanoparticles enhanced nanomotor accumulation in tumor cells. Subsequently, the nanomotors release Gox and gemcitabine, which significantly inhibit tumor progression.Conclusion: This innovative strategy utilizes gemcitabine - loaded nanomotors to penetrate the mucus layer and target tumors, inducing cell death for the treatment of bladder cancer.Keywords: bladder cancer, nanomotor, intravesical therapy