Achieving Precision Phototherapy from Start to Finish: Integrating Endosomal Escape, Respiration Inhibition, and ROS Release in a Single Upconversion Nanoparticle.

Precision phototherapy requires tight control over several therapeutic steps, which traditional methods often struggle to achieve. Here, this study reports an orthogonal trichromatic upconversion nanoparticle with a rather simple nanoarchitecture, NaErF4@NaYbF4@NaYbF4:Nd@NaYF4:Yb,Tm. Unlike conventional designs that rely on multiple activators and complicated multi-shelled structures (up to six nanoshells), the reported triple-shelled UCNPs utilize only two activator ions (Er3⁺ and Tm3⁺) but still enables to release red, green, and blue colors in response to three different NIR light excitations, thus significantly reducing structural complexity and synthetic workload. Integrating these UCNPs with photosensitizers and nitric oxide (NO) donors further achieve to a precision photodynamic therapy, which allows for step-wise control throughout the entire PDT process by independent activation of bioimaging, photochemical internalization, respiration prohibition via NO release, and ROS generation via specific light illuminations. Both in vitro and in vivo results demonstrate high efficiency of presented methodology, highlighting its great potential for NIR light-activated precision phototherapy.