Minimally Invasive Bladder Stimulation via Upconversion Nanoparticle-Mediated Optogenetics

Currently, there are no clinically proven alternative treatments for inducing or enhancing bladder contractions. In this study, we applied optogenetics to modulate bladder function, successfully inducing contractions with 475 nm blue light after transfecting channelrhodopsin-2 (ChR2) into bladder smooth muscle cells. However, it requires laparotomy and bladder exposure due to restricted tissue penetration of visible light. Hence, we developed a minimally invasive approach utilizing tissue penetrating near-infrared (NIR) light via upconversion nanoparticles (UCNPs) as an intermediary for bladder control. The core-shell UCNPs NaYF4:Yb/Tm@PEG were designed. Excited at 980 nm, UCNPs emitted predominantly at 475 nm, matching the excitation wavelength of ChR2. We reasoned the feasibility of the UCNPs-mediated optogenetics system for its efficacy and safety. In our experiment, we confirmed that the blue light emitted by UCNPs under NIR is sufficient to activate ChR2 and induce cation influx in bladder smooth muscle cells. Moreover, we confirmed that NIR has low cell toxicity and acceptable photothermal effects. No significant tissue toxicity of UNCPs was detected. Then, we performed ex vivo bladder pressure recording and in vivo cystometry 4 weeks after UCNPs injection and ChR2 transfection. An 8.0 W 980 nm transdermal illumination was delivered from the optical laser, with no need for invasive procedures to expose the bladder. The result showed that NIR successfully induced bladder contractions in the ChR2-transfected bladder with the intermediation of UCNPs. Compared with spontaneous voiding, NIR-induced voiding exhibited higher maximum detrusor pressure and micturition volume. These findings demonstrated that UCNPs-mediated optogenetics can serve as a minimally invasive approach to optical bladder control.