Smart down/upconversion nanomachines integrated with “AND” logic computation and enzyme-free amplification for NIR-II fluorescence-assisted precise and enhanced photodynamic therapy

Upconversion nanoparticles enable indirect activation of photodynamic therapy (PDT) using near-infrared (NIR) light, providing an excellent alternative for treating deep tumors. However, conventional NIR light-triggered PDT systems suffered from low spatiotemporal accuracy and restricted therapeutic efficiency in vivo. In this work, DNA logic circuits were functionally modified on down/upconversion nanoparticles (D/UCNPs) to construct smart down/upconversion nanomachines (D/UCNMs) for NIR light-triggered PDT toward target tumors. Upon dual inputs of tumor-associated GSH and TK1 mRNA, DNA logic circuits perform “AND” logic computation and initiate the toehold-mediated strand displacement reaction. Meanwhile, the quenched upconversion fluorescence was recovered and then the approaching photosensitizers were activated, leading to in situ output of singlet oxygen ((1)O(2)) for precise and enhanced PDT. Importantly, the biodistribution of the D/UCNMs in vivo could be visualized by second near-infrared (NIR-II) fluorescence imaging via the downconversion luminance of D/UCNPs, which further contributed to performing precise PDT. This work provides new insights into the development of precise and highly efficient PDT systems.